Topical compositions and methods for making and using same

ABSTRACT

The present invention relates to improved topical gel compositions comprising an active agent, and uses thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Continuation of U.S. application Ser. No.15/255,464, filed Sep. 2, 2016, which is a Continuation of U.S.application Ser. No. 14/764,545, filed Jul. 29, 2015, now U.S. Pat. No.9,452,173, which is a National Stage Entry of PCT/US2014/014098, filedJan. 31, 2014, which is a Continuation-in-part of U.S. application Ser.No. 13/941,201, filed Jul. 12, 2013, now U.S. Pat. No. 9,433,680, whichis a Continuation-in-part of U.S. application Ser. No. 13/756,392, filedJan. 31, 2013, now U.S. Pat. No. 8,778,365. Each application isincorporated by reference herein in its entirety.

FIELD

The present subject matter relates to improved topical pharmaceuticalcompositions comprising an active agent, and methods of making and usingsame to treat, ameliorate, or prevent a condition.

BACKGROUND

Topical compositions may be used to deliver an active agent for thetreatment of various conditions and diseases. Formulating topicalcompositions presents several challenges. For example, it may bedifficult to formulate topical compositions that will cause lessirritation upon application of the same as compared to other topicalcompositions comprising the same active agent or active agents. Inaddition, it may also be difficult to prepare storage stable topicalcompositions that cause little or no irritation. Accordingly, thereremains a need to develop more effective topical treatments.

SUMMARY

The present invention provides an improved gel composition for topicaltreatment. Provided formulations comprise an active agent, as describedin detail herein. Methods of utilizing a provided formulation aredescribed herein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graphical representation of the results obtained from arelease assay in vitro test.

FIG. 2 is a flow chart illustrating a representative process formanufacturing provided gel compositions.

FIG. 3 is a graphical representation of the results obtained from acumulative penetration assay in vitro test.

FIG. 4 is a graphical representation of the results obtained from arelease assay in vitro test of fluticasone propionate Formulations B, C,and D.

DETAILED DESCRIPTION OF THE INVENTION

As described above, there remains a need for improved topical gelcompositions that are significantly more effective than known topicalantifungal pharmaceutical compositions. The present invention providesgel compositions with surprisingly improved delivery of an active agent,which improved delivery allows for less frequent dosing and/or a shortercourse of treatment. In some embodiments, compositions described hereindramatically reduce irritation or stinging associated with existingformulations. Further, in some embodiments, presently described gelcompositions are effective for treating, inter alia, moccasin-type Tineapedis, which was, heretofore, generally only effectively treated by anoral antifungal medication.

Gel Compositions:

In some embodiments, gel compositions of the present invention arecomprised of:

(i) a first solvent;

(ii) optionally a second solvent;

(iii) a non-carbomer rheology modifier;

(iv) an active agent;

(v) optionally one or more solubizing agents; and optionally one or moreof: a diluent, a preservative, a pH adjuster, a chelating agent, acoloring agent, and a fragrance. Exemplary such gel compositions aredescribed in further detail below and herein.

In some embodiments, the present invention provides a gel composition,wherein the composition does not comprise a carbomer.

In some embodiments, the present invention provides a gel composition,wherein thegel composition is a water soluble gel composition. In someembodiments, the present invention provides a gel composition, whereinthe gel composition is not a water soluble gel composition.

In some embodiments, a provided gel composition has a viscosity oraverage viscosity of from about 30,000 to about 100,000 Centipoise(“cP”); from about 40,000 to about 90,000 cP; from about 50,000 to about80,000 cP; from about 55,000 to about 75,000 cP; from about 55,000 toabout 70,000 cP; from about 60,000 to about 70,000 cP; or from about60,000 to about 66,000 cP.

In some embodiments, a provided gel composition has a viscosity oraverage viscosity of from about 55,000 to about 70,000 centipoise (cP).

In some embodiments, a provided gel composition has a viscosity oraverage viscosity of from about 30,000 to about 100,000 centipoise (cP).

Definitions:

As used herein, the terms “administer,” “administering,” and“administration,” refer to any method which, in sound medical practice,delivers a provided composition, or an active agent contained therein,to a subject in such a manner as to provide a therapeutic effect.

The phrase “candidal onychomycosis” as used herein refers to a fungalyeast infection of the fingernails and/or toenails caused by a Candidaspp., including for example, Candida albicans and Candida parapsilosis.

The term “carbomer” as used herein refers to a polymer of acrylic acidcross-linked with a polyfunctional compound, hence, a poly (acrylicacid) or polyacrylate.

The term “chelating agent” as used herein refers to any knownpharmaceutically acceptable chelating agents. Suitable chelating agentscan include but are not limited to any one or more ofethylenediaminetetraacetic acid(EDTA) and derivatives thereof, ethyleneglycol-bis-(2-aminoethyl)-N,N,N′,N′-tetraacetic acid (EGTA) andderivatives thereof, cyclohexanediamine tetraacetic acid (CDTA) andderivatives thereof, hydroxyethylethylenediamine triacetic acid (HEDTA)and derivatives thereof, diethylenetriamine pentaacetic acid (DTPA) andderivatives thereof, dimercaptopropane sulfonic acid (DMPS) andderivatives thereof, dimercaptosuccinic acid (DMSA) and derivativesthereof, aminotrimethylene phosphonic acid (ATPA) and derivativesthereof, N,N-bis(carboxymethyl)glycine (NTA) and derivatives thereof,nitrilotriacetic acid and derivatives thereof, citric acid andderivatives thereof, niacinamide and derivatives thereof, sodiumdesoxycholate and derivatives thereof, polyphosphates; porphine; and anypharmaceutically acceptable salts thereof.

As used herein, the term “dermatomycosis” refers to a fungal infectionof the skin caused by a dermatophyte.

As used herein, the term “diluent” refers to water or saline.

As used herein, the phrases an “effective amount” or a “therapeuticallyeffective amount” of an active agent or ingredient, or pharmaceuticallyactive agent or ingredient, refer to an amount of the pharmaceuticallyactive agent sufficient enough to have a therapeutic effect uponadministration. Effective amounts of the pharmaceutically active agentwill vary with the kind of pharmaceutically active agent chosen, theparticular condition or conditions being treated, the severity of thecondition, the duration of the treatment, the specific components of thecomposition being used, and like factors. For example, the presentlydescribed compositions can be topically applied in an amount sufficientto cover an affected area plus a margin of healthy skin or tissuesurrounding the affected area, for example, a margin of about 0.5inches, at a frequency, for example, of once a day, for a time period,for example of about two weeks.

As used herein, the phrase “fungal infection” refers to any superficialfungal infection, including for example, one or more of a superficialfungal infection of the skin, onychomycosis, and a fungal infection of ahair follicle, each of which is as defined herein. Such fungalinfections can include superficial fungal infections of the skin,including for example, one or more of Tinea cruris, Tinea corporis,interdigital Tinea pedis, moccasin-type Tinea pedis, Tinea manuum, Tineaversicolor (pityriasis), Tinea nigra, cutaneous candidiasis, Tineafaciei, and white and black piedra; fungal infections of the hairfollicle including one or more of Tinea capitis, Tinea Favose (favus),and Tinea barbae; and onychomycosis, a fungal infection of one or moreof the nail bed, matrix, and nail plate, caused by, for example,dermatophytes, yeasts, and non-dermatophyte molds.

As used herein, the phrase “fungal infection of the hair follicle”refers to a fungal infection of at least the tubular infolding of theepidermis (skin) containing the root of a hair of any one or more of thescalp, eyebrows, eyelashes, and bearded area of an individual. Thephrase “fungal infection of the hair follicle” also refers to a fungalinfection of the tubular infolding of the epidermis (skin) containingthe root of a hair of any one or more of the scalp, eyebrows, eyelashes,and bearded area, along with a fungal infection of the hair shaft, of anindividual. Such fungal infections can include, for example, one or moreof Tinea capitis, Tinea favosa, and Tinea Barbae. The term “hairfollicle” refers to a tubular infolding of the epidermis (skin)containing the root of a hair. The follicle is lined by cells derivedfrom the epidermal layer of the skin. Tinea capitis (or severehighly-inflammatory cases sometimes termed Kerion) is a superficialfungal infection (dermatophytosis) of the skin of the scalp, eyebrows,and eyelashes, that attacks the hair follicles and shaft. The disease isprimarily caused by dermatophytes in the Trichophyton and Microsporumgenera, including for example, Microsporum audouini, Microsporum canis,Microsporum distortum, Microsporum gypseum, Trichophyton megninii,Trichophyton mentagrophytes, Trichophyton rubrum, Trichophytonschoenleinii, Trichophyton tonsurans, and Trichophyton verrucosum. Theclinical presentation is typically a single or multiple patches of hairloss, sometimes with a ‘black dot’ pattern (often with broken-offhairs), that may be accompanied by inflammation, scaling, pustules, anditching. Tinea favosa can be considered a variety of Tinea capitisbecause it involves the scalp; however, it may also involve glabrousskin and nails. Tinea favosa is primarily caused by dermatophytes in theTrichophyton and Microsporum genera, including for example, Microsporumgypseum and Trichophyton schoenleinii. Tinea barbae is a superficialdermatophytosis that is limited to the bearded areas of the face, neck,chin, cheeks, and/or lips and occurs almost exclusively in olderadolescent and adult males. The clinical presentation of Tinea barbaeincludes inflammatory, deep, kerion-like plaques and non-inflammatorysuperficial patches resembling Tinea corporis or bacterial folliculitis.The mechanism that causes Tinea barbae is similar to that of Tineacapitis, and is frequently the result of a Trichophyton rubrum (T.rubrum) infection but may also be the result of Trichophytonmentagrophytes var granulosum and Trichophyton verrucosum. FinallyMicrosporum canis and Trichophyton mentagrophytes var erinacei have beenknown to cause Tinea barbae but are relatively rare.

As used herein, the term “infection” refers to the invasion, developmentand/or multiplication of a microorganism within or on another organism.An infection may be localized to a specific region of an organism orsystemic.

The phrase “non-carbomer rheology modifier/thickener” as used hereinrefers to any known rheology modifier/thickener that is not a carbomer.Suitable non-carbomer rheology modifiers/thickeners can include but arenot limited to hydroxy celluloses, semi-synthetic polymers includingcarboxymethyl cellulose and starch; natural polysaccharides includingbut not limited to guar gum, locust bean gum, xanthan, chitosan andalginate. Suitable hydroxy celluloses include hydroxyethyl cellulose(HEC), hydroxymethyl cellulose (HMC), hydroxypropyl cellulose (HPC),hydroxypropylmethyl cellulose (HPMC), and hydroxyethylmethyl cellulose(HEMC).

The phrase “non-irritating,” as used herein, refers to the presentlydescribed topical pharmaceutical compositions, including for example,the presently described gel topical pharmaceutical compositions, thatelicit reduced irritation, for example, reduced burning and/or stinging,in a subject, for example, as compared to the irritation elicited byknown topical pharmaceutical compositions. For example, less than 5% ofsubjects treated with the presently described topical pharmaceuticalcomposition report irritation due to application of the pharmaceuticalcomposition, i.e., burning and/or stinging; less than 4% of subjectstreated with the presently described topical pharmaceutical compositionreport irritation due to application of the pharmaceutical composition;less than 3% of subjects treated with the presently described topicalpharmaceutical composition report irritation due to application of thepharmaceutical composition; less than 2% of subjects treated with thepresently described topical pharmaceutical composition report irritationdue to application of the pharmaceutical composition; or less than 1% ofsubjects treated with the presently described topical pharmaceuticalcomposition report irritation due to application of the pharmaceuticalcomposition. See the Examples and comparative Examples described herein.As used herein the term “pH adjuster” refers to any pharmaceuticallyacceptable composition, compound, or agent, suitable for adjusting thepH of the presently described topical pharmaceutical compositionswithout negatively affecting any property thereof. Suitable pH adjusterscan include any pharmaceutically acceptable acid or base. Suitable pHadjusters can include but are not limited to hydrochloric acid, sulfuricacid, citric acid, acetic acid, formic acid, phosphoric acid, tartricacid, trolamine, sodium hydroxide and potassium hydroxide.

The phrase “occlusive dressing or covering” as used herein refers to anyporous or non-porous dressing or covering that may retain moistureand/or heat, and/or may increase the concentration and/or absorption ofthe active agent being topically applied. Suitable occlusive coveringscan include, for example, a bandage, wrap, coban-type dressings,silicone-type bandages, foam bandages, duct tape, plastic wrap, latex,rubber, or other non-permeable material, a commercially availableadhesive bandage, gauze, a patch, an adhesive patch, a sock, and/or aglove or mitten.

The term “onychomycosis” as used herein refers to a fungal infection ofthe nail bed, matrix, and/or or nail plate. Onychomycosis is caused bythree main classes of fungi: dermatophytes, yeasts (candidalonychomycosis), and non-dermatophyte molds. Dermatophytes are the mostcommon cause of onychomycosis. Onychomycosis caused by non-dermatophytemolds is becoming more common worldwide. Onychomycosis due to Candida isless common. Dermatophytes that can cause onychomycosis include one ormore of Trichophyton rubrum, Trichophyton interdigitale, Epidermophytonfloccosum, Trichophyton violaceum, Microsporum gypseum, Trichophytontonsurans, Trichophyton soudanense, and Trichophyton verrucosum, andsuch disease is often also referred to as Tinea ungium. Candidalonychomycosis include cutaneous candidisis and mucocutaneouscandidiasis, that are caused by one or more Candida species, includingfor example, Candida albicans and Candida parapsilosis. Non-dermatophytemolds that can cause onychomycosis can include one or more of, forexample, Scopulariopsis brevicaulis, Fusarium spp., Aspergillus spp.,Alternaria, Acremonium, Scytalidinum dimidiatum, and Scytalidiniumhyalinum. There are four classic types of onychomycosis including thefollowing: distal and lateral subungal onychomycosis (DLSO) that is themost common form of onychomycosis, and is usually caused by Trichophytonrubrum and/or Trichophyton interdigitale, which invades the nail bed andthe underside of the nail plate; white superficial onychomycosis (WSO)is caused by fungal (e.g., T. mentagrophytes) invasion of thesuperficial layers of the nail plate to form “white islands” on theplate, non-dermatophyte molds cause deep white superficialonychomycosis; proximal subungal onychomycosis (PSO) is fungalpenetration of the newly formed nail plate through the proximal nailfold and it is the least common form of onychomycosis in healthy people,but is found more commonly when the patient is immunocompromised;endonyx onychomycosis (EO), and candidal onychomycosis (CO) which isCandida species invasion of the fingernails.

As used herein, the phrase “pharmaceutically acceptable salts” refers tosalts of certain ingredient(s) which possess the same activity as theunmodified compound(s) and which are neither biologically nor otherwiseundesirable. A salt can be formed with, for example, organic orinorganic acids. Such suitable acids include acetic acid,acetylsalicylic acid, adipic acid, alginic acid, ascorbic acid, asparticacid, benzoic acid, benzenesulfonic acid, bisulfic acid, boric acid,butyric acid, camphoric acid, camphorsulfonic acid, carbonic acid,citric acid, cyclopentanepropionic acid, digluconic acid, dodecylsulficacid, ethanesulfonic acid, formic acid, fumaric acid, glyceric acid,glycerophosphoric acid, glycine, glucoheptanoic acid, gluconic acid,glutamic acid, glutaric acid, glycolic acid, hemisulfic acid, heptanoicacid, hexanoic acid, hippuric acid, hydrobromic acid, hydrochloric acid,hydroiodic acid, hydroxyethanesulfonic acid, lactic acid, maleic acid,malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucicacid, naphthylanesulfonic acid, naphthylic acid, nicotinic acid, nitrousacid, oxalic acid, pelargonic, phosphoric acid, propionic acid,saccharin, salicylic acid, sorbic acid, succinic acid, sulfuric acid,tartaric acid, thiocyanic acid, thioglycolic acid, thiosulfuric acid,tosylic acid, undecylenic acid, and naturally and synthetically derivedamino acids.

As used herein the term “preservative” refers to any knownpharmaceutically acceptable preservative that functions by inhibitingbacteria, fungi, yeast, mold, other microbe, and/or by inhibitingoxidation. Suitable preservatives include but are not limited toantimicrobial agents and/or antioxidants. Suitable antimicrobial agentscan include but are not limited to benzoates, benzyl alcohol, sodiumbenzoate, sorbates, propionates, and nitrites. Suitable antioxidants caninclude but are not limited to vitamin C, butylated hydroxytoluene(BHT), sulphites, and vitamin E.

The term “prevent,” “preventing,” or “prevention,” as used herein refersto any reduction, no matter how slight, of a subject's predisposition orrisk for developing a condition, disease, disorder or symptom thereof.For purposes of prevention, the subject is any subject, and preferablyis a subject that is at risk for, or is predisposed to, developing acondition, disease, disorder. The term “prevention” includes eitherpreventing the onset of a clinically evident condition, disease,disorder altogether or preventing the onset of a pre-clinically evidentcondition, disease, disorder in individuals at risk. This includesprophylactic treatment of subjects at risk of developing condition,disease, disorder.

As used herein, the term “solvent” refers to any pharmaceuticallyacceptable medium which is a liquid at ambient temperature, in which oneor more solutes can be dissolved, or one or more substances can bepartially dissolved or suspended, which medium is present in a providedcomposition in an amount of about 10 wt % or more. Numerous solvents arewell known in the chemical and pharmaceutical arts and are contemplatedherein and below.

As used herein, the term “solubilizing agent” refers to anypharmaceutically acceptable liquid medium, surfactant, and/or emulsifierthat ispresent in a provided composition in an amount of less than about10 wt %. One of skill in the chemical and pharmaceutical arts willreadily appreciate that certain of the above-described solvents may alsobe used in substantially lower amounts such that they are characterizedherein as solubilizing agents rather than solvents. Accordingly, in someembodiments, a solubilizing agent is any one of the above-listedsolvents present in a provided formulation in an amount less than 10 wt% of the formulation. For example, in some embodiments, a solubilizingagent is a dialkylene glycol monoalkyl ether, such as, e.g., diethyleneglycol monoethyl ether, present in an amount of less than 10 wt %. Insome embodiments, a solubilizing agent is an alcohol, for instance,ethanol, present in an amount less than 10 wt %. Exemplary other suchsolubilizing agents are described below and herein.

The phrase “substantially pure” as used herein refers to an individualcompound form, which is substantially devoid of all other forms, as wellas degradation products of a form, and any residual solvent, and is atleast 85% pure on a % weight basis, unless otherwise specified. Thecompound form can have at least 90% purity on a % weight basis, at least93% purity on a % weight basis, at least 95% purity on a % weight basis,or at least 97%, 98%, 99%, or 99.5% purity on a % weight basis.

As used herein, “subject” or “individual” or “animal” or “patient” or“mammal,” refers to any subject, particularly a mammalian subject, forwhom diagnosis, prognosis, or therapy is desired, for example, a human.

As used herein, the term “superficial fungal infection of the skin”refers to a fungal infection present on the outer layer of skin,including Tinea cruris (jock itch), Tinea corporis (ringworm), Tineapedis, interdigital Tinea pedis, moccasin-type Tinea pedis, Tineamanuum, Tinea versicolor (piyriasis), Tinea nigra, cutaneouscandidiasis, Tinea faciei (facial ringworm), and white and black piedra.Tinea corporis (body ringworm), Tinea cruris (jock itch), and Tineafaciei (facial ringworm), can be caused by Epidermophyton floccosum,Microsporum canis, Trichophyton mentagrophytes, T. rubrum, T. tonsurans,T. verrucosum, and/or T. violaceum. Tinea pedis (athlete's foot) orTinea manuum (fungal infection of the hand), are caused byEpidermophyton floccosum, Microsporum canis, Trichophytonmentagrophytes, T. rubrum, T. tonsurans, T. verrucosum, and/or T.violaceum. Cutaneous candidiasis can be caused by C. albicans.

As used herein, a “treatment” or “treating” of a disease, disorder, orcondition encompasses alleviation of at least one symptom thereof, areduction in the severity thereof, or the delay or inhibition of theprogression thereof. Treatment need not mean that the disease, disorder,or condition is totally cured. A useful composition herein needs only toreduce the severity of a disease, disorder, or condition, reduce theseverity of symptoms associated therewith, provide improvement to apatient or subject's quality of life, or delay or inhibit the onset of adisease, disorder, or condition.

As used herein, all percentages are by weight of the total composition(i.e., wt %), unless otherwise specified.

Any concentration ranges, percentage range, or ratio range recitedherein are to be understood as expressly disclosing and including anyconcentrations, percentages or ratios of any integer within that rangeand fractions thereof, such as one tenth and one hundredth of aninteger, and any sub-range falling within a range, unless otherwiseindicated.

Any number range recited herein relating to any physical feature,including for example, polymer subunits, size or thickness, are to beunderstood as expressly disclosing and including any integer or fractionof an integer within a disclosed range, or any sub-range within adisclosed range, unless otherwise indicated.

For the purpose of clarity, any element or feature of any method orcomposition or process described herein, can be combined with any otherelement or feature of any other method or composition or processdescribed herein.

Other terms as used herein are meant to be defined by their well-knownmeanings in the art.

Solvents

As defined above, a gel composition of the present invention comprisesone or more solvents as described above and defined herein. Forinstance, in some embodiments, a provided gel composition comprises onlyone solvent, such as a glycol solvent (e.g., propylene glycol) or analkyl alcohol solvent (e.g., ethanol). In other embodiments, a gelcomposition of the present invention comprises more than one solvent. Insome embodiments wherein a gel composition of the present inventioncomprises more than one solvent, the present invention refers to one ofthe more than one solvents as a “first solvent” and another of the morethan one solvents as a “second solvent.” In such instances, by “firstsolvent” is meant any of the solvents described above and herein; by“second solvent” is meant any of the solvents described above and hereinother than the “first solvent.” Likewise, also contemplated herein areadditional solvents, e.g., a “third solvent,” a “fourth solvent,” etc.,which solvents are also characterized in that each is a differentsolvent from the others. In some embodiments, a first or second solventis, for example, a glycol solvent. In some embodiments, a first orsecond solvent is, for example, an alcohol solvent. Exemplary such oneor more solvents, and combinations thereof, are contemplated by thepresent invention and described herein.

In some embodiments, a solvent is an alcohol solvent. In certainembodiments, the alcohol solvent is an alkyl alcohol. Exemplary suchalcohol solvents include, but are not limited to, one or more ofmethanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol,t-butyl alcohol, 2-butanol, iso-butanol, pentanol, hexanol,cyclohexanol, and hexadecan-1-ol. In some embodiments, the alcoholsolvent is methanol, ethanol, n-propyl alcohol, or isopropyl alcohol. Incertain embodiments, the alcohol solvent is ethanol. In someembodiments, a solvent is a mixture of one or more such alcohols.

As used herein and unless otherwise indicated, the term “ethanol” refersto 190 proof USP grade ethanol. In some embodiments, USP grade ethanolis ethanol containing NLT 92.3% and NMT 93.8%, by weight, correspondingto NLT 94.9% and NMT 96.0%, by volume, at 15.56, of C₂H₅OH.

In some embodiments, a solvent is, e.g., a triacetin and/or diol and/orpolyol solvent. Diol solvents can include, but are not limited to,glycol solvents. In certain embodiments, a solvent is an alkylene glycolsolvent. For instance, in some embodiments, the alkylene glycol solventis ethylene glycol, propylene glycol, butylene glycol, or the like. Incertain embodiments, the glycol solvent is propylene glycol.

In some embodiments, a solvent is a glycol ether. For instance, in someembodiments, a solvent is a dialkylene glycol monoalkyl ether, such as,e.g., diethylene glycol monoethyl ether. Other such glycol ethers areknown in the chemical and pharmaceutical arts and are contemplated bythe present invention.

In some embodiments, a solvent is present in a gel composition in anamount greater than 10 wt % to about 50 wt %; from greater than 10 wt %to about 45 wt %; from greater than 10 wt % to about 35 wt %; fromgreater than 10 wt % to about 30 wt %; from greater than 10 wt % toabout 25 wt %; from greater than 10 wt % to about 20 wt %; from greaterthan 10 wt % to about 15 wt %; from about 15 wt % to about 30 wt %; fromabout 15 wt % to about 25 wt %; from about 15 wt % to about 20 wt %;from about 20 wt % to about 45 wt %; from about 25 wt % to about 45 wt%; from about 30 wt % to about 40 wt %; from about 16 wt % to about 24wt %; from about 17 wt % to about 23 wt %; from about 18 wt % to about24 wt %; from about 18 wt % to about 23 wt %; from about 18 wt % toabout 22 wt %; from about 18 wt % to about 21 wt %; from about 18 wt %to about 20 wt %; from about 18.5 wt % to about 19.5 wt %; from about 19wt % to about 20 wt %; from about 19 wt % to about 21 wt %; from about19 wt % to about 22 wt %; from about 19 wt % to about 23 wt %; fromabout 19 wt % to about 24 wt %; from about 19 wt % to about 25 wt %;about 11 wt %; about 12 wt %; about 13 wt %; about 14 wt %; about 15 wt%; about 16 wt %; about 17 wt %; about 18 wt %; about 19 wt %; about 20wt %; about 21 wt %; about 22 wt %; about 23 wt %; about 24 wt %; about25 wt %; about 26 wt %; about 27 wt %; about 28 wt %; about 29 wt %;about 30 wt %; about 31 wt %; about 32 wt %; about 33 wt %; about 34 wt%; about 35 wt %; about 36 wt %; about 37 wt %; about 38 wt %; about 39wt %; about 40 wt %; about 41 wt %; about 42 wt %; about 43 wt %; about44 wt %; or about 45 wt %.

In some embodiments, a solvent is present in a gel composition in anamount of from about 16 wt % to about 24 wt %. In some embodiments, asolvent is present in a gel composition in an amount of from about 17 wt% to about 23 wt %. In some embodiments, a solvent is present in a gelcomposition in an amount of from about 18 wt % to about 22 wt %. In someembodiments, a solvent is present in a gel composition in an amount offrom about 18 wt % to about 21 wt %. In certain embodiments, a solventis present in a gel composition in an amount of about 18 wt %. Incertain embodiments, a solvent is present in a gel composition in anamount of about 19 wt %. In certain embodiments, a solvent is present ina gel composition in an amount of about 20 wt %.

In some embodiments, a solvent is present in a gel composition in anamount of from about 20 wt % to about 45 wt %. In some embodiments, asolvent is present in a gel composition in an amount of from about 25 wt% to about 45 wt %. In some embodiments, a solvent is present in a gelcomposition in an amount of from about 30 wt % to about 45 wt %. In someembodiments, a solvent is present in a gel composition in an amount offrom about 35 wt % to about 45 wt %. In some embodiments, a solvent ispresent in a gel composition in an amount of about 35 wt %; about 36 wt%; about 37 wt %; about 38 wt %; about 39 wt %; about 40 wt %; about 41wt %; about 42 wt %; about 43 wt %; about 44 wt %; or about 45 wt %. Incertain embodiments, a solvent is present in a gel composition in anamount of about 41%.

In certain embodiments, a gel composition of the present inventioncomprises more than one solvent, wherein at least one of the more thanone solvents is a glycol solvent.

In certain embodiments, a gel composition of the present inventioncomprises more than one solvent, wherein at least one of the more thanone solvents is an alcohol solvent.

In certain embodiments, a gel composition of the present inventioncomprises more than one solvent, wherein at least one of the more thanone solvents is an alcohol solvent and one of the more than one solventsis a glycol solvent. In certain embodiments, an alcohol solvent and aglycol solvent are each present in an amount of about 15 wt % to about35 wt %. In certain embodiments, an alcohol solvent and a glycol solventare each present in an amount of about 15 wt % to about 30 wt %. Incertain embodiments, an alcohol solvent and a glycol solvent are eachpresent in an amount of about 15 wt % to about 25 wt %. In certainembodiments, an alcohol solvent and a glycol solvent are each present inan amount of about 18 wt % to about 21 wt %. In some embodiments, thealcohol solvent is an alkyl alcohol (e.g., ethanol) present in an amountof about 15-25 wt % and the glycol solvent is an alkylene glycol (e.g.,propylene glycol) present in an amount of about 15-25 wt %. In someembodiments, the alcohol solvent is ethanol and is present in an amountof about 18-20 wt % and the glycol solvent is propylene glycol and ispresent in an amount of about 18-20 wt %.

Solubilizing agent:

In some embodiments, a gel composition of the present inventioncomprises one or more solubilizing agents as described above and definedherein. For instance, in some embodiments, the one or more solubilizingagent is a polysorbate solubilizing agent. In some embodiments, the oneor more solubilizing agent is an alcohol solubilizing agent. In someembodiments, the one or more solubilizing agent is a dialkylene glycolmonoalkyl ether solubilizing agent. Exemplary solubilizing agents aredescribed below and herein.

In some embodiments, a solubilizing agent is a suitable surfactant oremulsifier. Suitable surfactants or emulsifiers include one or morenon-ionic surfactants, PEG-80 sorbitan laurate (2,3-dihydroxypropyloctanoate) (e.g., TWEEN 28), a polyoxyethylene co-solvent, andpolysorbate surfactants/emulsifiers.

In some embodiments, a solubilizing agent is a suitable surfactant. Incertain embodiments, a suitable surfactant is a polysorbate. Exemplarypolysorbate solubilizing agents include, but are not limited to,Polysorbate 20 (polyoxyethylen-(20)-sorbitanmonolaurate), Polysorbate 21(polyoxyethylen-(4)-sorbitanmonolaurate), Polysorb ate 25, Polysorbate40 (polyoxyethylen-(20)-sorbitanmonopalmitate), Polysorbate 41, Polysorbate 45, Polysorb ate 60 (polyoxyethylen-(20)-sorbitanmonostearate),Polysorbate 61 (polyoxyethylen-(4)-sorbitanmonostearate), Polysorbate 65(polyoxyethylen-(20)-sorbitantristearate), Polysorbate 80(polyoxyethylen-(20)-sorbitanmonooleate), Polysorbate 81(polyoxyethylen-(5)-sorbitanmonooleate), Polysorbate 85(polyoxyethylen-(20)-sorbitantrioleate), Polysorbate 120(polyoxyethylen-(20)-sorbitanmonoisostearate), Polysorbate 121, andPolysorbate 125.

In certain embodiments, the polysorbate solubilizing agent isPolysorbate 20 (polyoxyethylen-(20)-sorbitanmonolaurate), Polysorbate 40(polyoxyethylen-(20)-sorbitanmonopalmitate), Polysorb ate 60(polyoxyethylen-(20)-sorbitanmonostearate), Polysorbate 65(polyoxyethylen-(20)-sorbitantristearate), or Polysorbate 80(polyoxyethylen-(20)-sorbitanmonooleate).

In certain embodiments, the polysorbate solubilizing agent isPolysorbate 20 (polyoxyethylen-(20)-sorbitanmonolaurate). In certainembodiments, the polysorbate solubilizing agent is Polysorbate 80(polyoxyethylen-(20)-sorbitanmonooleate).

In some embodiments, a solubilizing agent is a glycol ether. In someembodiments, asolubilizing agent is a dialkylene glycol monoalkyl ether.In certain embodiments, a solubilizing agent is diethylene glycolmonoethyl ether. In some embodiments, a solubilizing agent is a glycolether present in an amount of less than about 8 wt %. In someembodiments, a solubilizing agent is a glycol ether present in an amountof less than about 7 wt %. In some embodiments, a solubilizing agent isa glycol ether present in an amount of less than about 6 wt %. In someembodiments, a solubilizing agent is a glycol ether present in an amountof less than about 5 wt %. In some embodiments, a solubilizing agent isa glycol ether, e.g., diethylene glycol monoethyl ether, present in anamount ranging from about 0.5 wt % to about 3.0 wt %.

In some embodiments, it is highly desirable that a provided gelcomposition elicit reduced irritation, for example, reduced burningand/or stinging, in a subject, for example, as compared to theirritation elicited by known topical pharmaceutical compositions.Accordingly, in some embodiments, the presently described gelcompositions do not comprise an alcohol solvent. Rather, in certainembodiments, a gel composition of the present invention comprisesalcohol in a reduced amount, for instance as a solubilizing agent. Incertain embodiments, a gel composition of the present inventioncomprises one or more solubilizing agents, wherein at least onesolubilizing agent is a polysorbate solubilizing agent and at least onesolubilizing agent is an alcohol solubilizing agent. In certainembodiments, a gel composition of the present invention comprises one ormore solubilizing agents, wherein at least one solubilizing agent is apolysorbate solubilizing agent and at least one solubilizing agent is adialkylene glycol monoalkyl ether solubilizing agent. In someembodiments, a gel composition of the present invention comprises apolysorbate solubilizing agent, an alcohol solubilizing agent, andoptionally a third solubilizing agent. For instance, in certainembodiments, a gel composition of the present invention comprises apolysorbate solubilizing agent (e.g., Polysorbate 20), an alcoholsolubilizing agent (e.g., an alkyl alcohol solvent such as ethanol), anda dialkylene glycol monoalkyl ether solubilizing agent (e.g., diethyleneglycol monoethyl ether). Exemplary other such one or more solubilizingagents, and combinations thereof, are contemplated by the presentinvention and are described herein.

In some embodiments, the solubilizing agent is present in an amount ofabout 0.5 wt %. In some embodiments, a solubilizing agent is present inan amount of about 0.75 wt %. In some embodiments, a solubilizing agentis present in an amount of about 1.0 wt %. In some embodiments, asolubilizing agent is present in an amount of about 1.25 wt %. In someembodiments, a solubilizing agent is present in an amount of about 1.5wt %. In some embodiments, a solubilizing agent is present in an amountof about 1.75 wt %. In some embodiments, a solubilizing agent is presentin an amount of about 2.0 wt %. In some embodiments, a solubilizingagent is present in an amount of about 2.25 wt %. In some embodiments, asolubilizing agent is present in an amount of about 2.5 wt %. In someembodiments, a solubilizing agent is present in an amount of about 2.75wt %. In some embodiments, a solubilizing agent is present in an amountof about 3.0 wt %. In some embodiments, a solubilizing agent is presentin an amount of about 3.25 wt %. In some embodiments, a solubilizingagent is present in an amount of about 3.5 wt %. In some embodiments, asolubilizing agent is present in an amount of about 3.75 wt %. In someembodiments, a solubilizing agent is present in an amount of about 4.0wt %. In some embodiments, a solubilizing agent is present in an amountof about 4.25 wt %. In some embodiments, a solubilizing agent is presentin an amount of about 4.5 wt %. In some embodiments, a solubilizingagent is present in an amount of about 4.75 wt %. In some embodiments, asolubilizing agent is present in an amount of about 5.0 wt %. In someembodiments, a solubilizing agent is present in an amount of about 6.0wt %. In some embodiments, a solubilizing agent is present in an amountof about 7.0 wt %. In some embodiments, a solubilizing agent is presentin an amount of about 8.0 wt %. In some embodiments, a solubilizingagent is present in an amount of about 9.0 wt %. In some embodiments, asolubilizing agent is present in an amount of less than about 10.0 wt %.

In some embodiments, a solubilizing agent is present in an amountranging from about 0.5 wt % to about 3.0 wt %. In some embodiments, asolubilizing agent is present in an amount ranging from about 1.0 wt %to about 2.0 wt %. In some embodiments, a solubilizing agent is presentin an amount of about 1.5 wt %.

In some embodiments, a solubilizing agent is present in an amountranging from about 4.0 wt % to about 9.0 wt %. In some embodiments asolubilizing agent is present in an amount ranging from about 4.5 wt %to about 9.0 wt %. In some embodiments, a solubilizing agent is presentin an amount ranging from about 5.0 wt % to about 9.0 wt %. In someembodiments, a solubilizing agent is present in an amount of about 5.0wt %. In some embodiments, a solubilizing agent is present in an amountof about 8.0 wt %. In certain embodiments, a solubilizing agent is analcohol solubilizing agent, e.g., ethanol, and is present in an amountof about 8.0 wt %.

Non-Carbomer Rheology Modifier:

The non-carbomer rheology modifier for use in the presently describedgel compositions can include any known rheology modifier/thickener thatis not a carbomer.

In some embodiments, the non-carbomer rheology modifier for use in thepresently described gel compositions can include any known rheologymodifier/thickener that is not an alkyl cellulose, e.g., ethylcellulose.

Suitable non-carbomer rheology modifiers/thickeners include hydroxycelluloses, semi-synthetic polymers including but not limited tocarboxymethyl cellulose and starch; natural polysaccharides includingbut not limited to guar gum, locust bean gum, xanthan, chitosan andalginate. Suitable hydroxy celluloses hydroxyethyl cellulose (HEC),hydroxymethyl cellulose (HMC), hydroxypropyl cellulose (HPC),hydroxyethylmethyl cellulose (HEMC), and hydroxypropylmethyl cellulose(HPMC).

In some embodiments, the non-carbomer rheology modifier is hydroxyethylcellulose (HEC) and is present in a described gel composition in anamount ranging from about 1.5 wt % to about 2.0 wt %. In certainembodiments, the hydroxyethylcelluose is present in an amount of about1.75 wt %.

One of skill in the relevant chemical and pharmaceutical arts willappreciate that hydroxycelluloses are available in a variety of chainlengths and that the amount required by a particular formulation mayvary depending on, inter alia, the chain length of the selectedhydroxycellulose. In some embodiments, the HEC has a viscosity ofbetween 100 and 25000 mPa's. In certain embodiments, the HEC has aviscosity of between 1500-2500 mPa's.

The described non-carbomer rheology modifiers/thickeners can be presentin the described gel compositions in an amount of from >0.5 wt % toabout 4 wt %; from >0.5 wt % to about 3 wt %; from >0.5 wt % to about2.5 wt %; from >0.5 wt % to about 2 wt %; from >0.5 wt % to about 2.25wt %; from >0.5 wt % to about 2 wt %; from about 0.5 wt % to about 4 wt%; from about 0.5 wt % to about 3 wt %; from about 0.5 wt % to about 2.5wt %; from about 0.5 wt % to about 2.25 wt %; from about 0.5 wt % toabout 2 wt %; from about 0.7 wt % to about 4 wt %; from about 0.7 wt %to about 3 wt %; from about 0.7 wt % to about 2.5 wt %; from about 0.7wt % to about 2.25 wt %; from about 0.7 wt % to about 2 wt %; from about0.9 wt % to about 4 wt %; from about 0.9 wt % to about 3 wt %; fromabout 0.9 wt % to about 2.5 wt %; from about 0.9 wt % to about 2.25 wt%; from about 0.9 wt % to about 2 wt %; from about 1 wt % to about 4 wt%; from about 1 wt % to about 3.5 wt %; from about 1 wt % to about 3 wt%; from about 1 wt % to about 2.5 wt %; from about 1 wt % to about 2.25wt %; from about 1.1 wt % to about 2.3 wt %; from about 1.3 wt % toabout 2.3 wt %; from about 1.4 wt % to about 1.7 wt %; from about 1.4 wt% to about 1.8 wt %; from about 1.4 wt % to about 1.9 wt %; from about1.4 wt % to about 2 wt %; from about 1.4 wt % to about 2.1 wt %; fromabout 1.4 wt % to about 2.2 wt %; from about 1.4 wt % to about 2.3 wt %;from about 1.5 wt % to about 1.8 wt %; from about 1.5 wt % to about 1.9wt %; from about 1.5 wt % to about 2 wt %; from about 1.5 wt % to about2.1 wt %; from about 1.5 wt % to about 2.2 wt %; from about 1.5 wt % toabout 2.3 wt %; from about 1.6 wt % to about 1.8 wt %; from about 1.6 wt% to about 1.9 wt %; from about 1.6 wt % to about 2 wt %; from about 1.6wt % to about 2.1 wt %; from about 1.6 wt % to about 2.2 wt %; fromabout 1.6 wt % to about 2.3 wt %; from about 1.65 wt % to about 1.75 wt%; from about 1.65 wt % to about 1.85 wt %; from about 1.7 wt % to about1.8 wt %; from about 1.7 wt % to about 1.9 wt %; from about 1.7 wt % toabout 2 wt %; from about 1.7 wt % to about 2.1 wt %; from about 1.7 wt %to about 2.2 wt %; from about 1.7 wt % to about 2.3 wt %; from about 1.7wt % to about 2.25 wt %; about 1.7 wt %; or about 1.75 wt % non-carbomerrheology modifier.

Preservatives:

The preservatives for use in the presently described gel compositionscan include those described herein, including any known pharmaceuticallyacceptable preservative that functions by inhibiting bacteria and/orfungi, and/or by inhibiting oxidation. Suitable preservatives caninclude but are not limited to antimicrobial agents and/or antioxidants.Suitable antimicrobial agents can include but are not limited tobenzoates, benzyl alcohol, sodium benzoate, sorbates, propionates, andnitrites. Suitable antioxidants can include but are not limited tovitamin C, butylated hydroxytoluene (BHT), sulphites, and vitamin E, aswell asany known pharmaceutically acceptable preservative. In certainembodiments, the preservative is benzyl alcohol.

The described preservatives and/or antioxidants can be present in thedescribed gel compositions in an amount of, for example, from about0.001 wt % to about 15 wt %; from about 0.01 wt % to about 5 wt %; fromabout 0.2 wt % to about 4 wt %; from about 0.3 wt % to about 4 wt %;from about 0.4 wt % to about 4 wt %; from about 0.5 wt % to about 4 wt%; from about 0.6 wt % to about 4 wt %; from about 0.7 wt % to about 3wt %; from about 0.8 wt % to about 2 wt %; from about 0.9 wt % to about1.5 wt %; from about 0.9 wt % to about 1.1 wt %; about 0.9 wt %; about 1wt %; or about 1.1 wt % preservative.

In certain embodiments, a gel composition of the present inventioncomprises benzyl alcohol in an amount ranging from about 0.9 wt % toabout 1.1 wt %. In certain embodiments, a gel composition of the presentinvention comprises benzyl alcohol in an amount of about 1.0 wt %. Insome embodiments, benzyl alcohol is absent from a gel composition of thepresent invention.

pH Adjusters:

pH adjusters for use in the presently described gel compositions caninclude any pharmaceutically acceptable composition, compound, or agent,suitable for adjusting the pH of the presently described topicalpharmaceutical compositions without negatively affecting any propertythereof. Suitable pH adjusters can include any pharmaceuticallyacceptable acid or base. Suitable pH adjusters include those describedherein.

In some embodiments, gel compositions of the present invention comprisea basic pH adjuster. For example, in certain embodiments, the pHadjuster is an amine base. Exemplary such amine bases are known in thechemical and pharmaceutical arts and include, e.g., triethanolamine(i.e., Trolamine). In certain embodiments, a gel composition of thepresent invention comprises from about 0.12 wt % to about 0.23 wt %triethanolamine. In certain embodiments, a gel composition of thepresent invention comprises from about 0.14 wt % to about 0.21 wt %triethanolamine. In certain embodiments, a gel composition of thepresent invention comprises from about 0.15 wt % to about 0.20 wt %triethanolamine. In certain embodiments, a gel composition of thepresent invention comprises from about 0.16 wt % to about 0.19 wt %triethanolamine. In certain embodiments, a gel composition of thepresent invention comprises about 0.17 wt % triethanolamine.

In some embodiments, a basic pH adjuster is hydroxide. In certainembodiments, the hydroxide is in the form of a salt of an alkali oralkaline earth metal. For instance, in some embodiments, a hydroxidesalt is sodium hydroxide, potassium hydroxide, or calcium hydroxide. Insome embodiments, a pH adjuster is carbonate. In certain embodiments,the carbonate is in the form of a salt of an alkali or alkaline earthmetal. For instance, in some embodiments, a carbonate salt is sodiumcarbonate, potassium carbonate, or calcium carbonate. Exemplary othersuch hydroxide and carbonate bases and the like are well-known in thechemical and pharmaceutical arts and contemplated herein.

The described pH adjusters can be present in a described gelcompositions in an amount of from >0.01 wt % to about 1 wt %; from >0.05wt % to about 1 wt %; from about 0.05 wt % to about 0.5 wt %; from about0.08 wt % to about 0.4 wt %; from about 0.08 wt % to about 0.35 wt %;from about 0.08 wt % to about 0.3 wt %; from about 0.08 wt % to about0.25 wt %; from about 0.09 wt % to about 0.4 wt %; from about 0.09 wt %to about 0.3 wt %; from about 0.09 wt % to about 0.25 wt %; from about0.1 wt % to about 0.25 wt %; from about 0.11 wt % to about 0.24 wt %;from about 0.12 wt % to about 0.23 wt %; from about 0.13 wt % to about0.22 wt %; from about 0.14 wt % to about 0.21 wt %; from about 0.15 wt %to about 0.2 wt %; from about 0.16 wt % to about 0.19 wt %; from about0.16 wt % to about 0.18 wt %; from about 0.165 wt % to about 0.175 wt %;about 0.16 wt %; about 0.17 wt %; or about 0.18 wt % pH adjuster.

In some embodiments, a presently described gel composition has a pH offrom about 4.0 to about 7.5; from about 4.0 to about 7.0; from about 4.0to about 6.5; from about 4.0 to about 6.0; from about 4.5 to about 6.5;from about 4.5 to about 6.0; from about 4.5 to about 5.5; from about 4.7to about 5.5;; from about 4.8 to about 5.4; or from about 4.7 to about5.5, from about 4.9 to about 5.3; from about 4.5 to about 6.0; fromabout 4.6 to about 5.9; from about 4.7 to about 5.8; from about 4.8 toabout 5.7; from about 4.9 to about 5.6; from about 5.0 to about 5.4;from about 5.1 to about 5.3; from about 5.5 to about 7.5; from about 5.6to about 7.4; from about 5.7 to about 7.3; from about 5.8 to about 7.2;from about 5.9 to about 7.1; from about 6.0 to about 7.0; from about 6.1to about 6.9; from about 6.2 to about 6.8; from about 6.3 to about 6.7;from about 6.4 to about 6.6; about 4.5; about 4.6; about 4.7; about 4.8;about 4.9; about 5.0; about 5.1; about 5.2; about 5.3; about 5.4; about5.5; about 5.6; about 5.7; about 5.8; about 5.9; about 6.0, about 6.1,about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4,or about 7.5. For example, the pH of the presently described gelcomposition comprising 2 wt % active agent, for example naftifinehydrochloride at 23° C.±2° C. can be from about 4.5 to about 6.0.

In some embodiments, a presently described gel composition has a pH offrom about 6.5 to about 8.5. In some embodiments, a presently describedgel composition has a pH of about 6.5, about 6.6, about 6,7, about 6.7,about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about7.5, about 7.5, about 7.6; about 7.7; about 7.8; about 7.9; about 8.0;about 8.1; about 8.2; about 8.3; about 8.4; or about 8.5. For example,the pH of the presently described gel composition comprising 0.025 wt %active agent, for example fluticasone propionate at 23° C.±2° C. can befrom about 7.5 to about 8.5.

Chelating Agents:

Chelating agents for use in the presently described gel compositions caninclude any known pharmaceutically acceptable chelating agents. Suitablechelating agents can include but are not limited to any one or more ofethylenediaminetetraacetic acid(EDTA), cyclohexanediamine tetraaceticacid (CDTA), hydroxyethylethylenediamine triacetic acid (HEDTA),diethylenetriamine pentaacetic acid (DTPA), dimercaptopropane sulfonicacid (DMPS), dimercaptosuccinic acid (DMSA), aminotrimethylenephosphonic acid (ATPA), polyphosphates; porphine; and anypharmaceutically acceptable salt thereof. In certain embodiments, asuitable chelating agent is disodium EDTA (i.e., edetate disodium).

The described chelating agents can be present in the described topicalpharmaceutical compositions in an amount of, for example, from about0.001 wt % to about 10 wt %; from about 0.005 wt % to about 5 wt %; fromabout 0.005 wt % to about 0.5 wt %; from about 0.001 wt % to about 1 wt%; from about 0.01 to about 5 wt %; from about 0.006 wt % to about 0.04wt %; from about 0.007 wt % to about 0.035 wt %; from about 0.008 wt %to about 0.035 wt %; from about 0.009 wt % to about 0.035 wt %; fromabout 0.01 wt % to about 0.03 wt %; from about 0.015 wt % to about 0.025wt %; from about 0.018 wt % to about 0.022 wt %; from about 0.019 wt %to about 0.021 wt %; about 0.019 wt %; about 0.02 wt %; or about 0.021wt % chelating agent.

In certain embodiments, a gel composition of the present inventioncomprisesfrom about 0.01 wt % to about 0.03 wt % disodium EDTA (i.e.,edetate disodium). In certain embodiments, a gel composition of thepresent invention comprisesfrom about 0.015 wt % to about 0.025 wt %disodium EDTA (i.e., edetate disodium). In certain embodiments, a gelcomposition of the present invention comprisesfrom about 0.017 wt % toabout 0.023 wt % disodium EDTA (i.e., edetate disodium). In certainembodiments, a gel composition of the present invention comprisesabout0.02 wt % disodium EDTA (i.e., edetate disodium).

Active Agents

The presently described pharmaceutical compositions may comprise anactive agent and/or a pharmaceutically acceptable salt thereof. Theactive agent may be present in the topical pharmaceutical compositionsin an amount of from 0.01 wt % to about 10 wt %; from 0.01 wt % to about9 wt %; from 0.01 wt % to about 8 wt %; from 0.01 wt % to about 7 wt %;from 0.01 wt % to about 6 wt %; from 0.01 wt % to about 5 wt %; from0.01 wt % to about 4.5 wt %; from 0.01 wt % to about 4 wt %; from 0.01wt % to about 3.5 wt %; from 0.01 wt % to about 3 wt %; from 0.01 wt %to about 2.5 wt %; from 0.01 wt % to about 2 wt %; from 0.01 wt % toabout 2.25 wt %; from 0.01 wt % to about 2 wt %; from about 0.01% toabout 4 wt %; from about 0.01 wt % to about 3 wt %; from about 0.01 wt %to about 2.5 wt %; from about 0.01 wt % to about 2.25 wt %; from about0.01 wt % to about 2 wt %; from about 0.01 wt % to about 1.5 wt %; fromabout 0.01 wt % to about 1 wt %; from about 0.01 wt % to about 0.5 wt %;from 0.1 wt % to about 10 wt %; from 0.1 wt % to about 9 wt %; from 0.1wt % to about 8 wt %; from 0.1 wt % to about 7 wt %; from 0.1 wt % toabout 6 wt %; from 0.1 wt % to about 5 wt %; from 0.1 wt % to about 4.5wt %; from 0.1 wt % to about 4 wt %; from 0.1 wt % to about 3.5 wt %;from 0.1 wt % to about 3 wt %; from 0.1 wt % to about 2.5 wt %; from 0.1wt % to about 2 wt %; from 0.1 wt % to about 2.25 wt %; from 0.1 wt % toabout 2 wt %; from about 0.1% to about 4 wt %; from about 0.1 wt % toabout 3 wt %; from about 0.1 wt % to about 2.5 wt %; from about 0.1 wt %to about 2.25 wt %; from about 0.1 wt % to about 2 wt %; from about 0.1wt % to about 1.5 wt %; from about 0.1 wt % to about 1 wt %; from about0.1 wt % to about 0.5 wt %; from 0.7 wt % to about 10 wt %; from 0.7 wt% to about 9 wt %; from 0.7 wt % to about 8 wt %; from 0.7 wt % to about7 wt %; from 0.7 wt % to about 6 wt %; from 0.7 wt % to about 5 wt %;from 0.7 wt % to about 4.5 wt %; from 0.7 wt % to about 4 wt %; from 0.7wt % to about 3.5 wt %; from 0.7 wt % to about 3 wt %; from 0.7 wt % toabout 2.5 wt %; from 0.7 wt % to about 2 wt %; from 0.7 wt % to about2.25 wt %; from 0.7 wt % to about 2 wt %; from about 0.7 % to about 4 wt%; from about 0.7 wt % to about 3 wt %; from about 0.7 wt % to about 2.5wt %; from about 0.7 wt % to about 2.25 wt %; from about 0.7 wt % toabout 2 wt %; from about 0.7 wt % to about 1.5 wt %; from about 0.7 wt %to about 1 wt %; from 0.9 wt % to about 10 wt %; from 0.9 wt % to about9 wt %; from 0.9 wt % to about 8 wt %; from 0.9 wt % to about 7 wt %;from 0.9 wt % to about 6 wt %; from 0.9 wt % to about 5 wt %; from 0.9wt % to about 4.5 wt %; from 0.9 wt % to about 4 wt %; from 0.9 wt % toabout 3.5 wt %; from 0.9 wt % to about 3 wt %; from 0.9 wt % to about2.5 wt %; from 0.9 wt % to about 2 wt %; from 0.9 wt % to about 2.25 wt%; from 0.9 wt % to about 2 wt %; from about 0.9 % to about 4 wt %; fromabout 0.9 wt % to about 3 wt %; from about 0.9 wt % to about 2.5 wt %;from about 0.9 wt % to about 2.25 wt %; from about 0.9 wt % to about 2wt %; from about 0.9 wt % to about 1.5 wt %; from about 0.9 wt % toabout 1 wt %; from 1 wt % to about 10 wt %; from 1 wt % to about 9 wt %;from 1 wt % to about 8 wt %; from 1 wt % to about 7 wt %; from 1 wt % toabout 6 wt %; from 1 wt % to about 5 wt %; from 1 wt % to about 4.5 wt%; from 1 wt % to about 4 wt %; from 1 wt % to about 3.5 wt %; from 1 wt% to about 3 wt %; from 1 wt % to about 2.5 wt %; from 1 wt % to about 2wt %; from 1 wt % to about 2.25 wt %; from 1 wt % to about 2 wt %; fromabout 1% to about 4 wt %; from about 1 wt % to about 3 wt %; from about1 wt % to about 2.5 wt %; from about 1 wt % to about 2.25 wt %; fromabout 1 wt % to about 2 wt %; from about 1 wt % to about 1.5 wt %; fromabout 1.5 wt % to about 10 wt %; from about 1.5 wt % to about 9 wt %;from about 1.5 wt % to about 8 wt %; from about 1.5 wt % to about 7 wt%; from about 1.5 wt % to about 6 wt %; from about 1.5 wt % to about 5wt %; from about 1.5 wt % to about 4.5 wt %; from about 1.5 wt % toabout 4 wt %; from about 1.5 wt % to about 3.5 wt %; from about 1.5 wt %to about 3 wt %; from about 1.5 wt % to about 2.5 wt %; %; from about1.5 wt % to about 2.25 wt %; from about 1.5 wt % to about 2 wt %; fromabout 3 wt % to about 10 wt %; from about 3 wt % to about 9 wt %; fromabout 3 wt % to about 8 wt %; from about 3 wt % to about 7 wt %; fromabout 3 wt % to about 6 wt %; from about 3 wt % to about 5 wt %; fromabout 3 wt % to about 4.5 wt %; from about 3 wt % to about 4 wt %; fromabout 3 wt % to about 3.5 wt %; or in any other amount within any of theabove ranges.

In some embodiments, the active agent or pharmaceutically acceptablesalt thereof may be present in the topical pharmaceutical compositionsin an amount of from 0.01 wt % to about 1.0 wt %; from about 0.01 wt %to about 0.9 wt %; from about 0.01 wt % to about 0.85 wt %; from about0.01 wt % to about 0.8 wt %; from about 0.01 wt % to about 0.75 wt %;from about 0.01 wt % to about 0.70 wt %; from about 0.01 wt % to about0.65 wt %; from about 0.01 wt % to about 0.60 wt %; from about 0.01 wt %to about 0.55 wt %; from about 0.01 wt % to about 0.50 wt %; from about0.01 wt % to about 0.45 wt %; from about 0.01 wt % to about 0.40 wt %;from about 0.01 wt % to about 0.35 wt %; from about 0.01 wt % to about0.30 wt %; from about 0.01 wt % to about 0.25 wt %; from about 0.01 wt %to about 0.20 wt %; from about 0.01 wt % to about 0.15 wt %; from about0.01 wt % to about 0.10 wt %; from about 0.015 wt % to about 0.1 wt %;from about 0.02 wt % to about 0.1 wt %; from about 0.025 wt % to about0.1 wt %; from about 0.03 wt % to about 0.1 wt %; from about 0.035 wt %to about 0.1 wt %; from about 0.04 wt % to about 0.1 wt %; from about0.045 wt % to about 0.1 wt %; from about 0.05 wt % to about 0.1 wt %;from about 0.06 wt % to about 0.1 wt %; from about 0.07 wt % to about0.1 wt %;

from about 0.08 wt % to about 0.1 wt %; from about 0.09 wt % to about0.1 wt %; or in any other amount within any of the above ranges.

In some embodiments, the active agent or pharmaceutically acceptablesalt thereof is present in a gel composition in an amount of from about0.01 wt % to about 0.06 wt %; from about 0.015 wt % to about 0.055 wt %;from about 0.015 wt % to about 0.05 wt %; or from about 0.02 wt % toabout 0.05 wt %. In some embodiments, the active agent orpharmaceutically acceptable salt thereof may be present in an amount ofabout 0.025 wt %. In some embodiments, the active agent orpharmaceutically acceptable salt thereof may be present in an amount ofabout 0.05 wt %. In some embodiments the active agent orpharmaceutically acceptable salt thereof may be present in an amount ofabout 0.01 wt %, 0.015wt %, 0.02 wt %, 0.025 wt %, 0.03 wt %, 0.035 wt%, 0.04 wt %, 0.045 wt %, 0.05 wt %, 0.055 wt %, 0.06 wt %, 0.065 wt %,0.07 wt %, 0.075 wt %, 0.08 wt %, 0.085 wt %, 0.09 wt %, 0.095 wt %, or0.1 wt %.

The described active agent and/or a pharmaceutically acceptable saltthereof can be present in a gel composition of the present invention inan amount of from about 0.05 wt % to about 6.0 wt %, of from about 0.1wt % to about 6.0 wt %, of from about 0.5 wt % to about 6.0 wt %, offrom about 0.6 wt % to about 6.0 wt %, of from about 0.7 wt % to about6.0 wt %, of from about 0.8 wt % to about 6.0 wt %, of from about 0.9 wt% to about 6.0 wt %, of from about 1.0 wt % to about 6.0 wt %, of fromabout 1.5 wt % to about 6.0 wt %, of from about 2.0 wt % to about 6.0 wt%, of from about 2.5 wt % to about 6.0 wt %, of from about 3.0 wt % toabout 6.0 wt %, of from about 3.5 wt % to about 6.0 wt %, of from about4.0 wt % to about 6.0 wt %, of from about 4.5 wt % to about 6.0 wt %, offrom about 5.0 wt % to about 6.0 wt %, of from about 5.5 wt % to about6.0 wt %, of from about 0.05 wt % to about 3.0 wt %, of from about 0.1wt % to about 2.9 wt %, of from about 0.2 wt % to about 2.7 wt %, offrom about 0.3 wt % to about 2.5 wt %, of from about 0.4 wt % to about2.3 wt %, of from about 0.5 wt % to about 2.1 wt %, of from about 0.6 wt% to about 1.9 wt %, of from about 0.7 wt % to about 1.7 wt %, of fromabout 0.8 wt % to about 1.5 wt %, of from about 0.9 wt % to about 1.3 wt%, of from about 1 wt % to about 1.1 wt %, of from about 0.05 wt % toabout 1.0 wt %, of from about 0.06 wt % to about 1.0 wt %, of from about0.07 wt % to about 1.0 wt %, of from about 0.08 wt % to about 1.0 wt %,of from about 0.09 wt % to about 1.0 wt %, of from about 0.1 wt % toabout 1.0 wt %, of from about 0.15 wt % to about 1.0 wt %, of from about0.2 wt % to about 1.0 wt %, of from about 0.25 wt % to about 1.0 wt %,of from about 0.3 wt % to about 1.0 wt %, of from about 0.35 wt % toabout 1.0 wt %, of from about 0.4 wt % to about 1.0 wt %, of from about0.45 wt % to about 1.0 wt %, of from about 0.5 wt % to about 1.0 wt %,of from about 0.55 wt % to about 1.0 wt %, of from about 0.6 wt % toabout 1.0 wt %, of from about 0.65 wt % to about 1.0 wt %, of from about0.7 wt % to about 1.0 wt %, of from about 0.75 wt % to about 1.0 wt %,of from about 0.8 wt % to about 1.0 wt %, of from about .85 wt % toabout 1.0 wt %, of from about 0.9 wt % to about 1.0 wt %, of from about0.95 wt % to about 1.0 wt %, of from about 0.5 wt % to about 4.0 wt %,of from about 0.75 wt % to about 4.0 wt %, of from about 1 wt % to about4.0 wt %, of from about 1.25 wt % to about 4.0 wt %, of from about 1.5wt % to about 4.0 wt %, of from about 2 wt % to about 4.0 wt %, of fromabout 2.25 wt % to about 4.0 wt %, of from about 2.5 wt % to about 4.0wt %, of from about 2.75 wt % to about 4.0 wt %, of from about 3 wt % toabout 4.0 wt %, of from about 3.75 wt % to about 4.0 wt %, of from about1.5 wt % to about 3.0 wt %, from about 1.5 wt % to about 2.5 wt %, fromabout 1.6 wt % to about 2.4 wt %, from about 1.7 wt % to about 2.3 wt %,from about 1.75 wt % to about 2.25 wt %, from about 1.8 wt % to about2.2 wt %, from about 1.9 wt % to about 2.1 wt %, about 2.0 wt %, about2.5 wt %, from about 1.9 wt % to about 3.0 wt %, from about 2.0 wt % toabout 3.0 wt %, from about 2.1 wt % to about 3.0 wt %, from about 2.2 wt% to about 3.0 wt %, from about 2.3 wt % to about 3.0 wt %, from about2.4 wt % to about 3.0 wt %, from about 2.5 wt % to about 3.0 wt %, fromabout 2.6 wt % to about 3.0 wt %, from about 2.7 wt % to about 3.0 wt %,from about 2.8 wt % to about 3.0 wt %, from about 2.9 wt % to about 3.0wt %, about 3.0 wt %, 2.0 wt %, 2.5 wt %, or 3.0 wt %.

Antibacterial Agents

In some embodiments, the active agent or pharmaceutically acceptablesalt thereof is an antibacterial agent. In some embodiments, theantibacterial agent is, for example, bacitracin, polymyxin (B),neomycin, muprirocin, retapamulin, gentamycin, silver sulfadiazine,benzol peroxide, hydrogen peroxide, clindamycin phosphate, erythromycin,minocycline, doxycyclinemetronidazole, azelaic acid, sodiumsulfacetamide, sodium sulfacetamide sulfur, dapsone (diamino-diphenylsulfone), neramexane, penicillins, cephalosporins, carbapenems,monobactams, chloramphenicol, fluoroquinolones, tetracyclines,glycylcylines, macrolides, ketolide (telithromycin), daptomycin,linezolid, metronidazole, dalfopristin-quinupristin,trimethoprim-sulfamethoxazole, spectinomycin, vancomycin, fosfomycin,cycloserine, lincosamides, aminoglycosides, colistin, novobiocin,metronidazole, sulfonamides, capreomycin, and kanamycin.

In some embodiments, an active agent or pharmaceutically acceptable saltthereof is an antiseptic agent including, e.g., detergents, bleaches,triclosan, chlorohexidine and povidone/iodine.

Antifungal Agents

In some embodiments, the active agent or pharmaceutically acceptablesalt thereof is an antifungal agent. For example, in some embodiments,the antifungal agent is a polyene, an azole, an allylamine (forinstance, naftifine or terbinafine) a benzyl amine (for instance,butenafine), or other antifungal agents (for instance, amorolfine).Examples of polylenes include, e.g, nystatin and Amphotericin B.Examples of azoles include miconazole, clotrimazole, ketoconazole,oxiconazole, eberconazole, econazole, sulconazole and sertaconazlebifonazole, butoconazole, fenticonazole, isoconazole, omoconazole andtioconazole, or pharmaceutically acceptable salts thereof. Exemplaryother antifungals include include naftifine, terbinafine and butenafine,or pharmaceutically acceptable salts. Still other antifungal agentsinclude, e.g., ciclopirox or selenium sulfide. Additional antifungalsinclude agents that block NA synthesis including, e.g., flucytosine, andthose that disrupt microtubule function including, e.g., griseofulvin.Suitable antifungals can include one of candicidin, filipin, hamycin,natamycin, and rimocidin. Triazoles, including albaconazole,fluconazole, isavuconazole, itraconazole, posaconazole, ravuconazole,terconazole, and voriconazole are also suitable antifungal activeagents. Also suitable are, thiazoles including, e.g., abafungin.Suitable antifungal agents include, e.g., of amorolfin, butenafine,naftifine, and terbinafine. In addition, echinocandins, includinganidulafungin, caspofungin, and micafungin, are suitable antifungals.Also suitable are griseofulvin, benzoic acid, ciclopirox, haloprogin,polygodial, tolnaftate, undecylenic acid, and Crystal violet.

Suitable antifungal agents for use in the present topical pharmaceuticalcompositions include, but are not limited to, natifine, butenafine,terbinafine, and amorolfine, as well as any pharmaceutically acceptablesalts thereof. Suitable salts of antifungal agents include but are notlimited to hydrochloride salts. In some embodiments, certain antifungalagents or pharmaceutically acceptable salts thereof are believed to actby interfering with squalene 2,3-epoxidase, which results in decreasedamounts of the principal membrane sterols, especially ergosterol.

Naftifine and pharmaceutically acceptable salts thereof have fungicidalactivity against organisms, including but not limited to, dermatophytes,including for example, Trichophyton rubrum, Trichophyton interdigitale,Trichophyton verrucosum, Trichophyton mentagrophytes, Trichophytonmegninii, Trichophyton tonsurans, Trichophyton schoenleinii,Trichophyton soudanense, Trichophyton violaceum, Epidermophytonfloccosum, Microsporum audouini, Microsporum canis, Microsporumdistortum, Microsporum gypseum; nondermatophyte molds including, forexample, Scopulariopsis brevicaulis, Fusarium spp., Aspergillus spp.,Alternaria, Acremonium, Scytalidinum dimidiatum, and Scytalidiniumhyalinum; and Candida spp. including, for example, Candida albicans, andCandida parapsilosis.

Butenafine and pharmaceutically acceptable salts thereof, for example,butenafine hydrochloride, have fungicidal activity against organisms,including but not limited to, dermatophytes, including for example,Trichophyton rubrum, Trichophyton mentagrophytes, Trichophytontonsurans, Epidermophyton floccosum, Microsporum canis; nondermatophytemolds including, for example, Aspergillus spp.; Candida spp. including,for example, Candida albicans and Candida parapsilosis; Malasseziafurfur; and Cryptococcus.

Terbinafine and pharmaceutically acceptable salts thereof, for example,terbinafine hydrochloride, is active against many fungi, includingdermatophytes (Trichophyton, Microsporum, Epidermophyton), filamentous(e.g. Aspergillus), dimorphic (e.g., Blastomyces), and dematiaceousfungi and yeasts. Terbinifine has an antifungal spectrum of activitysimilar to that of naftifine. More specifically, Terbinafine andpharmaceutically acceptable salts thereof, for example, butenafinehydrochloride, have fungicidal activity against organisms, including butnot limited to, dermatophytes, including for example, Trichophytonrubrum, Trichophyton mentagrophytes, Trichophyton tonsurans,Trichophyton violaceum, Epidermophyton floccosum, Microsporum audouini,Microsporum canis; nondermatophyte molds including, for example,Aspergillus spp. and Scopulariopsis brevicaulis; Candida spp. including,for example, Candida albicans and Candida parapsilosis; Blastomyces; andHistoplasma.

Amorolfine and pharmaceutically acceptable salts thereof, for example,amorolfine hydrochloride, is active against many fungi, includingdermatophytes (Trichophyton, Microsporum, Epidermophyton), filamentous(e.g. Aspergillus), dimorphic (e.g., Blastomyces and Sporothrixschenckii), dematiaceous fungi and yeasts, and Sporothrix schenckii.Amorolfine and pharmaceutically acceptable salts thereof, for example,amorolfin hydrochloride, have fungicidal activity against organisms,including but not limited to, dermatophytes including, for example,Trichophyton rubrum, Trichophyton mentagrophytes, Epidermophytonfloccosum; nondermatophyte molds including, for example, Scopulariopsisspp. including Scopulariopsis brevicaulis, Fusarium spp. includingFusarium solani, Aspergillus spp. including Aspergillus flavus, andAcremonium spp.; Candida spp. including, for example, Candida albicansand Candida parapsilosis; and Malassezia spp. including Malasseziafurfur.

In some embodiments, an antifungal agent is selected from the groupconsisting of naftifine, butenafine, terbinafine, and amorolfine. Insome embodiments, the antifungal agent is butenafine. In someembodiments, the antifungal agent is terbinafine. In some embodiments,the antifungal agent is amorolfine.

Methods for making the presently described antifungal agents andpharmaceutically acceptable salts thereof are disclosed in U.S. Pat.Nos: 4,755,534; 4,680,291; and 4,282,251, each of which is incorporatedby reference herein in its entirety.

Antiparasitics

In some embodiments, the active agent or pharmaceutically acceptablesalt thereof is an anti-parasitic agent. For example, in someembodiments, the anti-parasitic agent is permethrin, ivermectin,pyrethrins, lindane, malathion, benzyl benzoate, thiabendazole ordiiodohydroxyquinoline (iodoquinol).

Immune Enhancing Agents

Additionally, the active agent or pharmaceutically acceptable saltthereof is an immune enhancing agent. For example, the immune enhancingagent may be imiquimod or interferon. In some embodiments, the activeagent or pharmaceutically acceptable salt thereof is ananti-tumor/oncology or chemotherapeutic agents. For example, theanti-tumor agent may bemechlorethamine (chlormethine) or other similaralkylating agents, cisplatin, carboplatin, oxaliplatin,cyclophosphamide, chlorambucil, ifosfamide, vinca alkaloids and taxanessuch as vincristine, vinblastine, vinorelbine, vindesine, bexarotene,etoposide and teniposide, and topoisomerase inhibitors including type Itopoisomerase inhibitors such as camptothecins:

irinotecan and topotecan or type II inhibitors including amsacrine,etoposide, etoposide phosphate, and teniposide.

Cytodestructive Aagents

In some embodiments, an active agent, or pharmaceutically acceptablesalt thereof is a cytodestructive agent. Examples of cytodestructiveagents include, e.g., bleomycin, podophyllin/podofilox, trichloroaceticacid, canthadrin, salicylic acid, 5-fluorouracil and ingenol mebutate.

Hormonal Agents

In some embodiments, an active agent, or pharmaceutically acceptablesalt thereof is a hormonal agent, including, e.g., spironolactone,aldactone and finasteride.

In some embodiments, an active agent or pharmaceutically acceptable saltthereof is a sex hormone including, e.g., estogens, estriol, estradiol,estrone, testosterone, methyltestosterone, progesterone,medroxyprogesterone, hydroxyprogesterone, norethindrone and megesterol.

Calcineurin Inhibitors

In some embodiments, an active agent, or pharmaceutically acceptablesalt thereof is a calcineurin inhibitor, for example, tacrolimus andpimecrolimus.

Steroid Agents

In some embodiments, an active agent, or pharmaceutically acceptablesalt thereof is a steroid agent. In some embodiments, the steroid agentis a hydrocortisone type steroid, including, e.g., hydrocortisone,hydrocortisone acetate, hydrocortisone butyrate, cortisone acetate,tixocortol pivalate, prednisolone, methylprednisolone, or prednisone. Insome embodiments, the steroid agent is an acetonide or relatedsubstances including, e.g., triamcinolone acetonide, triamcinolonealcohol, mometasone, amcinonide, budesonide, desonide, fluocinonide,fluocinolone acetonide, or halcinonide. In some embodiments, the steroidagent is a betamethasone type steroid agent, including, e.g.betamethasone, betamethasone sodium phosphate, dexamethasone,dexamethasone sodium phosphate, or fluocortolone. In some embodiments,the steroid agent is an a halogenated (less labile) steroid, including,e.g., hydrocortisone-17-valerate, aclometasone dipropionate,betamethasone valerate, betamethasone dipropionate, prednicarbate,clobetasone-17-butyrate, clobetasol-17-propionate, fluocortolonecaproate, fluocortolone pivalate, or fluprednidene acetate. In someembodiments, the steroid agent is a labile prodrug ester, including,e.g., hydrocortisone-17-butyrate, 17-aceponate, 17-buteprate, andPrednicarbate. Additional steroids according to the present subjectmatter include, e.g., flunisolide, fluticasone, fluticasone propionate,amcinonide, clocortolone pivalate, halobetasol, desoximetasone andbeclomethasone dipropionate and fludroxycortide (also known asflurandrenolone or flurandrenolide). In some embodiments, the steroidagent is fluticasone in the form of fluticasone propionate orfluticasone furoate. In some embodiments, the steroid agent isfluticasone in the form of any suitable prodrug ester. As used herein,the phrase “fluticasone or a pharmaceutically acceptable salt thereof”refers to any pharmaceutically acceptable form of fluticasone, e.g.,salts or esters thereof.

Retinoid Agent

In some embodiments, an active agent or pharmaceutically acceptable saltthereof is a retinoid agent, including, e.g., retinol, retinal,tretinoin (retinoic acid, Retin-A), isotretinoin, alitretinoin,etretinate and its metabolite acitretin, tazarotene, bexarotene andadapalene.

Vitamin Analogs

In some embodiments, an active agent or pharmaceutically acceptable saltthereof is a vitamin analog, including e.g., a vitamin D3 syntheticanalog, calcipotriene, the naturally occurring form calcitriol.

Non-Steroidal Anti-Inflammatory Agents

In some embodiments, an active agent or pharmaceutically acceptable saltthereof is a non-steroidal anti-inflammatory (NSAID) drug. Examples ofNSAIDS include, e.g., aspirin, salsalate, ibuprofen, naproxen, acidderivatives, COX-2 inhibitors, and LOX/COX inhibitors. Examples of acidderivatives include, e.g., diclofenac, piroxicam and mefenamic acid.Examples of COX-2 inhibitors include, e.g., celecoxib and rofecoxib. Anexample of a LOX/COX inhibitor is licofelone.

In some embodiments, an active agent or pharmaceutically acceptable saltthereof is a non-steroidal anti-inflammatory agent including, e.g.,fenoprofen, ibuprofen, flurbiprofen, ketoprofen, naproxen, oxaprozin,diclofenac, etodalac, indomethacin, ketorolac, nabumetone, sulindac,tolmentin, meclofenamate, flufenamic acid, mefenamic acid, meclofenamicacid, piroxicam, salicylates, diflunisal, indomethacin, phenylbutazone,oxyphenbutazone, sulfinpyrazone, allopurinol, penicillamin, colchicineand probenicid.

Topical Contact Allergen

In some embodiments, an active agent or pharmaceutically acceptable saltthereof is a topical contact allergen including, e.g., squaric aciddibutyl ester (SADBE), diphenylcyclopropenone (DPC) ordinitrochlorobenzene (DNCB).

Skin Cosmetic Active Agent

In some embodiments, an active agent or pharmaceutically acceptable saltthereof is a skin cosmetic active agent. Non-limiting examples of skincosmetic active agents include, e.g., hydroquinone, arbutin,deoxyarbutin, dihydroxyacetone (DHA), oxymetazolin, brimonidine,epinephrine, plant extracts, aloe, caffeine, cocoa, tea extract,primrose oil, vitamins, vitamin analogs, eflornithine hydrochloride,alpha hydroxy acids (AHA), ammonium lactate, glycolic acids, coal tar,sinecatechins, surfactants and cleansers. Plant extracts include, e.g.,arnica and allium extract.

In some embodiments, an active agent or pharmaceutically acceptable saltthereof is a sunscreen. Examples of sunscreens include, e.g., zincoxide, avobenzone, octinoxate, oxybenzone, titanium dioxide, trolaminesalicylate and ensulzole.

In some embodiments, an active agent or pharmaceutically acceptable saltthereof is a keratolytic agent, including, e.g., urea, salicyclic acid,sulfur, and tar/coal tar.

In some embodiments, an active agent or pharmaceutically acceptable saltthereof is a vitamin. Examples of vitamins include, e.g., vitamin A,vitamin D, vitamin E, vitamin B1, vitamin B2, vitamin B3, vitamin B6,vitamin B12, vitamin C, multivitamin preparations and vitamincombinations.

Nasal Decongestants

In some embodiments, an active agent or pharmaceutically acceptable saltthereof is a nasal decongestant including, e.g., phenylpropanolamine,pseudoephedrine, phenylephrine, ephedrine, naphazoline, oxymetazoline,tetrahydrozoline, xylometazoline amd propylhexedrine.

Miscellaneous

In some embodiments, an active agent or pharmaceutically acceptable saltthereof is a miscellaneous agent including, e.g., finasteride,lamsoprazole, papaverine and prostaglandins.

Antirheumatic Aagents

In some embodiments, an active agent or pharmaceutically acceptable saltthereof is an antirheumatic agent including, e.g., gold compounds,penicillamine, azathioprine and methotrexate.

Gout Agents

In some embodiments, an active agent or pharmaceutically acceptable saltthereof is an agent for gout including, e.g., probenecid,sulfinpyrazone, allopurinol and colchicine.

Pain Management Agents

In some embodiments, an active agent or pharmaceutically acceptable saltthereof is a pain management agent including, e.g., a nonopiod analgesic(acetaminophen, aspirin, choline magnesium trisalicylate, NSAIDs,tramadol (opioid & nonopioid)), an opioid analgesic (codeine,dihydrocodeine, hydrocodone, oxycodone, morphine, hydromorphone,fentanyl), or an analgesic adjuvant used to enhance the effect of ananalgesic or counteract side effects of such (tricyclic antidepressants,benzodiazepines, caffeine, corticosteroids, anticonvulsants).

In some embodiments, an active agent or pharmaceutically acceptable saltthereof is an analgesic agent including, e.g., codeine, hydrocodone,hydromorphone, morphine, oxymorphone, oxycodone, meperidine, methadone,propoxyphene, tramadol, acetaminophen, pentazocine and fentanylsalicylates.

Antimycobacterial Agents

In some embodiments, an active agent or pharmaceutically acceptable saltthereof is an antimycobacterial including, e.g., isoniazide, rifamycin(rifabutin, rifampin, rifapentine), pyrazinamide, ethambutol,fluoroquinolones (moxifloxacin, levofloxacin, ciprofloxacin),aminoglycosides (streptomycin, amikacin, amikamycin, kanamycin),azithromycin, clarithromycin, capreomycin, rifampicin, nalidixic acid,ciprofloxacin, ofloxacin, p-aminosalicyclic acid, isoniazid,ethionamide, cycloserine, clofazimine, macrolides (clarithromycin,azithromycin), doxycycline, tigecycline, trimethoprim-sulfamethoxazole,amikacin, tobramycin, imipenem, linezolid, and cefoxitin.

Sulfonamide Agents

In some embodiments, an active agent or pharmaceutically acceptable saltthereof is a sulfonamide including, e.g., sulfadiazine, sulfacytine,sulfamethoxazole and suflamethiazole.

Antituberculosis Agents

In some embodiments, an active agent or pharmaceutically acceptable saltthereof is an antituberculous drug including isoniazid, rifampin,rifabutin, ethambutol HCl, pyrazinamide, aminosalicylate, sodiumethionamide, cycloserine, streptomycin sulfate, capreomycin.

Amebicide Agents

In some embodiments, an active agent or pharmaceutically acceptable saltthereof is an amebicide including, e.g.,paromomycin, iodoquinol,metronidazole, emetine and chloroquine.

Antiviral Agents

In some embodiments, an active agent or pharmaceutically acceptable saltthereof is an antiviral including, e.g., acyclovir, pencyclovir,cidofovir, idoxuridine, stavudine, zidovudine, ribavarin, amantadine,foscarnet, didanosine, acyclovir, ganciclovir, cidofovir, zalcitabine,rimantadine, calacyclovir, famiciclovir, abacavir, didanosine,emtricitabine, lamivudine, stavudine, tenofovir, zalcitabine,zidovudine, zidovudine-lamivudine, TRIZIVIR (zidovudine, lamivudine,abacavir), EPZICOM (aba-cavir-lamivudine), TRUVADA(tenofovir-emtricitabine), efavirenz, nevirapine, and delavirdine,amprenavir, atazanavir, fosamprenavir, indinavir, lopinavir-ritonavir,nelfinavir, ritonavir, saquinavir, and tipranavir

Anti-Influenza

In some embodiments, an active agent or pharmaceutically acceptable saltthereof is an anti-influenza agent including, e.g., rimatadine,amantadine, oseltamivir, and zanamivir.

Anti-Infective Agents

In some embodiments, an active agent or pharmaceutically acceptable saltthereof is a miscellaneous anti-infective including, e.g., trimethoprim,trimethoprim-sulfamethoxazole, erythromycin-sulfisoxazole, furazolidone,pentamidine, eflornithine, atovaquone, trimetrexate and glucuronate.

In some embodiments, an active agent or pharmaceutically acceptable saltthereof is aleprostatics including dapsone and clofazime.

Antihelmintic Agents

In some embodiments, an active agent or pharmaceutically acceptable saltthereof is an antihelmintic agent including, e.g., mebendazole,diethylcarbamazine citrate, pyrantel, thiabendazole, piperazine,quinacrine, niclosamide, oxamniquine and praziquantel.

Antihistamine Agents

In some embodiments, an active agent or pharmaceutically acceptable saltthereof is an antihistamine including, e.g., diphenhydramine,chlorpheniramine, pyrilamine, doxepin, carbinoxamine, clemastine,tripelennamine, brompheniramine, dexchlorpheniranune, triprolidine,methdilazine, promethazine, trimeprazine, hydroxyzine HCl, azatadine,cyproheptadine, phenindamine, astemizole, loratadine, terfenadine andcetirizine.

Antimetabolite Agent

In some embodiments, an active agent or pharmaceutically acceptable saltthereof is an antimetabolite agent including, e.g., 5-fluorouracil,6-mercaptopurine, mycophenolic acid, methotrexate, cytarabine,floxuridineand thioguanine.

Anticholinergic Agent

In some embodiments, an active agent or pharmaceutically acceptable saltthereof is an anticholinergic agent including e.g., atropine,bornaprine, glycopyrrolate, scopolamine, homatropine, tropatepine,tropicamide, pirenzepine, isopropamide, propantheline, methscopolamine,methantheline, trihexyphenidyl, benztropine and biperiden.

Steroidal Anti-Inflammatory Agents

In some embodiments, an active agent or pharmaceutically acceptable saltthereof is a steroidal anti-inflammatory agent including e.g.,cortisone, hydrocortisone, hydrocortisone acetate, prednisone,prednisolone, triamcinolone, methylprednisolone, dexamethasone,betamethasone, clobetasol, diflorasone, halobetasol, amicinonide,desoximetasone, fluocinolone, halcinonide, clocortolone,flurandrenolide, fluticasone, mometasone, aclometasone, desonide, andfludrocortisone. In some embodiments, the active agent is fluticasone.

Local Anesthetic Agents

In some embodiments, an active agent or pharmaceutically acceptable saltthereof is alocal anesthetic including e.g., dibucaine, lidocaine,benzocaine, butamben, picrate, tetracaine, dyclonine, pramoxine andprilocaine.

Sunscreen Agents

In some embodiments, an active agent or pharmaceutically acceptable saltthereof is a sunscreen agent including, e.g., oxybenzone, dioxybenzone,p-aminobenzoic acid, ethyl dihydroxy propyl PABA, padimate 0, glycerylPABA, cinoxate, ethylhexyl p-methoxycinnamate, octocrylene, octylmethoxycinnamate, ethylhexyl salicylate, homosalate, octyl salicylate,menthyl anthranilate, digalloyl trioleate and avobenzone.

Muscle Relaxants

In some embodiments, an active agent or pharmaceutically acceptable saltthereof is a muscle relaxant including, e.g.,carisoprodol,chlorphenesin, chlorzoxazone, cyclobenzaprine, metaxalone,methocarbamol, orphenadrine, diazepam and baclofen.

Exemplary Gel Compositions Containing an Active Agent

In some embodiments, the present invention provides a gel compositioncomprising any of the above-described active agents in any of the abovedescribed amounts. In some embodiments, the active agent is anantifungal agent as described above. In certain embodiments, theantifungal agent is naftifine (e.g., naftifine hydrochloride). In someembodiments, the active agent is a steroid as described above. Incertain embodiments, the active agent is a corticosteroid such asfluticasone (e.g., fluticasone propionate).

In some embodiments, the present invention provides a gel compositioncomprising or consisting essentially of:

(i) an active agent;

(ii) a first solvent;

(iii) optionally a second solvent;

(iv) a non-carbomer rheology modifier; and optionally one or more of: asolubilizing agent, a diluent, a preservative, a pH adjuster, achelating agent, a coloring agent, and a fragrance. Exemplary suchactive agents, solvents, non-carbomer rheology modifiers, solubilizingagents, diluents, preservatives, pH adjusters, and chelating agents, aredescribed above and herein. Exemplary such gel compositions aredescribed in further detail below and herein.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of from about 0.01 wt % to about6.0 wt % of an active agent or a pharmaceutically acceptable saltthereof, from about 10 wt % to about 25 wt % of a first solvent, fromabout 10 wt % to about 25 wt % of a second solvent, from about 0.75 wt %to about 2.25 wt % of a non-carbomer rheology modifier, and optionallyone or more of:a solubilizing agent, a diluent, a pH adjuster, achelating agent, a preservative, a fragrance, and a coloring agent.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of from about 0.01 wt % to about6.0 wt % of an active agent or a pharmaceutically acceptable saltthereof, from about 15 wt % to about 25 wt % of a first solvent, fromabout 15 wt % to about 25 wt % of a second solvent, from about 0.75 wt %to about 2.25 wt % of a non-carbomer rheology modifier, and optionallyone or more of:a solubilizing agent, a diluent, a pH adjuster, achelating agent, a preservative, a fragrance, and a coloring agent.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of from about 0.01 wt % to about4.0 wt % of an active agent or a pharmaceutically acceptable saltthereof, from about 15 wt % to about 25 wt % of a first solvent, fromabout 15 wt % to about 25 wt % of a second solvent, from about 0.75 wt %to about 2.25 wt % of a non-carbomer rheology modifier, and optionallyone or more of: a solubilizing agent, a diluent, a pH adjuster, achelating agent, a preservative, a fragrance, and a coloring agent.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of from about 0.01 wt % to about4.0 wt % an active agent or a pharmaceutically acceptable salt thereof,from about 15 wt % to about 25 wt % of a glycol solvent, from about 15wt % to about 25 wt % of an alcohol solvent; from about 0.75 wt % toabout 2.25 wt % of a hydroxy cellulose, and optionally one or more of: asolubilizing agent, a diluent, a pH adjuster, a chelating agent, apreservative, a fragrance, and a coloring agent.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of from about 0.01 wt % to about4.0 wt % of an active agent or a pharmaceutically acceptable saltthereof, from about 15 wt % to about 25 wt % of a glycol solvent, fromabout 15 wt % to about 25 wt % of an alcohol solvent, from about 0.75 wt% to about 2.25 wt % of a hydroxy cellulose, from about 3 wt % to about8 wt % of a solubilizing agent, and optionally one or more of: asolubilizing agent, a diluent, a pH adjuster, a chelating agent, apreservative, a fragrance, and a coloring agent.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of from about 0.01 wt % to about4.0 wt % of an active agent or a pharmaceutically acceptable saltthereof, from about 15 wt % to about 25 wt % propylene glycol, fromabout 15 wt % to about 25 wt % ethanol, from about 0.75 wt % to about2.25 wt % hydroxyethyl cellulose, from about 3 wt % to about 8 wt %Polysorbate 20, and optionally one or more of: a solubilizing agent, adiluent, a pH adjuster, a chelating agent, a preservative, a fragrance,and a coloring agent. In certain embodiments, a provided gel compositionis as described above, with the exception that Polysorbate 20 isreplaced with Polysorbate 80.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of an active agent orpharmaceutically acceptable salt thereof, in an amount of from about0.01 wt % to about 4.0 wt %, propylene glycol in an amount of from about18 wt % to about 22 wt %, ethanol in an amount of from about 17 wt % toabout 21 wt %, hydroxyethyl cellulose in an amount of from about 1.5 wt% to about 2 wt %, Polysorbate 20 in an amount of from about 4 wt % toabout 6 wt %, and optionally one or more of: a solubilizing agent, adiluent, a pH adjuster, a chelating agent, a preservative, a fragrance,and a coloring agent. In certain embodiments, a provided gel compositionis as described above, with the exception that Polysorbate 20 isreplaced with Polysorbate 80.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of an active agent orpharmaceutically acceptable salt thereof, in an amount of from about0.01 wt % to about 4.0 wt %, propylene glycol in an amount of from about18 wt % to about 22 wt %, ethanol in an amount of from about 17 wt % toabout 21 wt %, hydroxyethyl cellulose in an amount of from about 1.5 wt% to about 2 wt %, Polysorbate 20 in an amount of from about 4 wt % toabout 6 wt %, water, and optionally one or more of: a solubilizingagent, a pH adjuster, a chelating agent, a preservative, a fragrance,and a coloring agent. In certain embodiments, a provided gel compositionis as described above, with the exception that Polysorbate 20 isreplaced with Polysorbate 80.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of an active agent orpharmaceutically acceptable salt thereof, in an amount of from about0.01 wt % to about 4.0 wt %, propylene glycol in an amount of from about19 wt % to about 21 wt %, ethanol in an amount of from about 18 wt % toabout 20 wt %, hydroxyethyl cellulose in an amount of from about 1.6 wt% to about 1.9 wt %, and optionally one or more of: a solubilizingagent, a diluent, a pH adjuster, a chelating agent, a preservative, afragrance, and a coloring agent.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of an active agent orpharmaceutically acceptable salt thereof, in an amount of from about0.01 wt % to about 4.0 wt %, propylene glycol in an amount of from about19 wt % to about 21 wt %, ethanol in an amount of from about 18 wt % toabout 20 wt %, hydroxyethyl cellulose in an amount of from about 1.6 wt% to about 1.9 wt %, Polysorbate 20 in an amount of from about 4.5 wt %to about 5.5 wt %, water, and optionally one or more of: a pH adjuster,a chelating agent, a preservative, a fragrance, and a coloring agent. Incertain embodiments, a provided gel composition is as described above,with the exception that Polysorbate 20 is replaced with Polysorbate 80.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of an active agent orpharmaceutically acceptable salt thereof, in an amount of from about0.01 wt % to about 4.0 wt %, propylene glycol in an amount of from about19.5 wt % to about 20.5 wt %, ethanol in an amount of from about 18.5 wt% to about 19.5 wt %, hydroxyethyl cellulose in an amount of from about1.7 wt % to about 1.8 wt %, Polysorbate 20 in an amount of from about4.75 wt % to about 5.25 wt %, and optionally one or more of: a diluent,a pH adjuster, a chelating agent, a preservative, a fragrance, and acoloring agent. In certain embodiments, a provided gel composition is asdescribed above, with the exception that Polysorbate 20 is replaced withPolysorbate 80.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of an active agent orpharmaceutically acceptable salt thereof, in an amount of from about0.01wt % to about 4.0 wt %, propylene glycol in an amount of from about19.5 wt % to about 20.5 wt %, ethanol in an amount of from about 18.5 wt% to about 19.5 wt %, hydroxyethyl cellulose in an amount of from about1.7 wt % to about 1.8 wt %, Polysorbate 20 in an amount of from about4.75 wt % to about 5.25 wt %, water, and optionally one or more of: a pHadjuster, a chelating agent, a preservative, a fragrance, and a coloringagent. In certain embodiments, a provided gel composition is asdescribed above, with the exception that Polysorbate 20 is replaced withPolysorbate 80.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of an active agent orpharmaceutically acceptable salt thereof in an amount of from about 0.01wt % to about 4.0 wt %, about 20 wt % propylene glycol, about 19 wt %ethanol, about 1.75 wt % hydroxyethyl cellulose, about 5 wt %Polysorbate 20,water, and optionally one or more of: a pH adjuster, achelating agent, a preservative, a fragrance, and a coloring agent. Incertain embodiments, a provided gel composition is as described above,with the exception that Polysorbate 20 is replaced with Polysorbate 80.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of an active agent orpharmaceutically acceptable salt thereof in an amount of from about 0.01wt % to about 4.0 wt %, about 20 wt % propylene glycol, about 19 wt %ethanol, about 1.75 wt % hydroxyethyl cellulose, about 5 wt %Polysorbate 20, water, trolamine, ethylenediaminetetracetic acid (EDTA)or a salt thereof, benzyl alcohol, and optionally one or more of: afragrance, and a coloring agent. In certain embodiments, a provided gelcomposition is as described above, with the exception that Polysorbate20 is replaced with Polysorbate 80.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of an active agent orpharmaceutically acceptable salt thereof in an amount of from about 0.01wt % to about 4.0 wt %, about 20 wt % propylene glycol, about 19 wt %ethanol, about 5 wt % Polysorbate 20, about 1.75 wt % hydroxyethylcellulose, about 0.17 wt % trolamine, about 0.02 wt %ethylenediaminetetracetic acid (EDTA) or a salt thereof, about 1 wt %benzyl alcohol, water, and optionally one or more members selected fromthe group consisting of a fragrance and a coloring agent. In certainembodiments, a provided gel composition is as described above, with theexception that Polysorbate 20 is replaced with Polysorbate 80.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of an active agent orpharmaceutically acceptable salt thereof in an amount of from about 0.01wt % to about 4.0 wt %, about 20 wt % propylene glycol, about 19 wt %ethanol, about 5 wt % Polysorbate 20, about 1.75 wt % hydroxyethylcellulose, about 0.17 wt % trolamine, about 0.02 wt %ethylenediaminetetracetic acid (EDTA) or a salt thereof, about 1 wt %benzyl alcohol, and water. In certain embodiments, a provided gelcomposition is as described above, with the exception that Polysorbate20 is replaced with Polysorbate 80.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of an active agent orpharmaceutically acceptable salt thereof in an amount of from about 1.0wt % to about 3.0 wt %, about 20 wt % propylene glycol, about 19 wt %ethanol, about 5 wt % Polysorbate 20, about 1.75 wt % hydroxyethylcellulose, about 0.17 wt % trolamine, about 0.02 wt %ethylenediaminetetracetic acid (EDTA) or a salt thereof, about 1 wt %benzyl alcohol, and water. In certain embodiments, a provided gelcomposition is as described above, with the exception that Polysorbate20 is replaced with Polysorbate 80.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of an active agent orpharmaceutically acceptable salt thereof in an amount of about 2.0 wt %,about 20 wt % propylene glycol, about 19 wt % ethanol, about 5 wt %Polysorbate 20, about 1.75 wt % hydroxyethyl cellulose, about 0.17 wt %trolamine, about 0.02 wt % ethylenediaminetetracetic acid (EDTA) or asalt thereof, about 1 wt % benzyl alcohol, and water. In certainembodiments, a provided gel composition is as described above, with theexception that Polysorbate 20 is replaced with Polysorbate 80.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of from about 0.01 wt % to about3.0 wt % of an active agent or a pharmaceutically acceptable saltthereof, from about 10 wt % to about 25 wt % of a first solvent, fromabout 10 wt % to about 25 wt % of a second solvent, from about 0.75 wt %to about 2.25 wt % of a non-carbomer rheology modifier, and optionallyone or more of: a solubilizing agent, a diluent, a pH adjuster, achelating agent, a preservative, a fragrance, and a coloring agent.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of from about 0.01 wt % to about3.0 wt % of an active agent or a pharmaceutically acceptable saltthereof, from about 15 wt % to about 25 wt % of a first solvent, fromabout 15 wt % to about 25 wt % of a second solvent, from about 0.75 wt %to about 2.25 wt % of a non-carbomer rheology modifier, and optionallyone or more of: a solubilizing agent, a diluent, a pH adjuster, achelating agent, a preservative, a fragrance, and a coloring agent.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of from about 0.01 wt % to about2.0 wt % of an active agent or a pharmaceutically acceptable saltthereof, from about 15 wt % to about 25 wt % of a first solvent, fromabout 15 wt % to about 25 wt % of a second solvent, from about 0.75 wt %to about 2.25 wt % of a non-carbomer rheology modifier, and optionallyone or more of: a solubilizing agent, a diluent, a pH adjuster, achelating agent, a preservative, a fragrance, and a coloring agent.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of from about 0.01 wt % to about2.0 wt % an active agent or a pharmaceutically acceptable salt thereof,from about 15 wt % to about 25 wt % of a glycol, from about 15 wt % toabout 25 wt % of an alcohol solvent; from about 0.75 wt % to about 2.25wt % of a hydroxy cellulose, and optionally one or more of: asolubilizing agent, a diluent, a pH adjuster, a chelating agent, apreservative, a fragrance, and a coloring agent.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of from about 0.01 wt % to about2.0 wt % of an active agent or a pharmaceutically acceptable saltthereof, from about 15 wt % to about 25 wt % of a glycol solvent, fromabout 15 wt % to about 25 wt % of an alcohol solvent, from about 0.75 wt% to about 2.25 wt % of a hydroxy cellulose, from about 3 wt % to about8 wt % of a solubilizing agent, and optionally one or more of: asolubilizing agent, a diluent, a pH adjuster, a chelating agent, apreservative, a fragrance, and a coloring agent.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of from about 0.01 wt % to about2.0 wt % of an active agent or a pharmaceutically acceptable saltthereof, from about 15 wt % to about 25 wt % propylene glycol, fromabout 15 wt % to about 25 wt % ethanol, from about 0.75 wt % to about2.25 wt % hydroxyethyl cellulose, from about 3 wt % to about 8 wt %Polysorbate 20, and optionally one or more of: a solubilizing agent, adiluent, a pH adjuster, a chelating agent, a preservative, a fragrance,and a coloring agent.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of an active agent orpharmaceutically acceptable salt thereof, in an amount of from about0.01 wt % to about 2.0 wt %, propylene glycol in an amount of from about18 wt % to about 22 wt %, ethanol in an amount of from about 17 wt % toabout 21 wt %, hydroxyethyl cellulose in an amount of from about 1.5 wt% to about 2 wt %, Polysorbate 20 in an amount of from about 4 wt % toabout 6 wt %, and optionally one or more of: a solubilizing agent, adiluent, a pH adjuster, a chelating agent, a preservative, a fragrance,and a coloring agent.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of an active agent orpharmaceutically acceptable salt thereof, in an amount of from about0.01 wt % to about 2.0 wt %, propylene glycol in an amount of from about18 wt % to about 22 wt %, ethanol in an amount of from about 17 wt % toabout 21 wt %, hydroxyethyl cellulose in an amount of from about 1.5 wt% to about 2 wt %, Polysorbate 20 in an amount of from about 4 wt % toabout 6 wt %, water, and optionally one or more of: a solubilizingagent, a pH adjuster, a chelating agent, a preservative, a fragrance,and a coloring agent.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of an active agent orpharmaceutically acceptable salt thereof, in an amount of from about0.01 wt % to about 2.0 wt %, propylene glycol in an amount of from about19 wt % to about 21 wt %, ethanol in an amount of from about 18 wt % toabout 20 wt %, hydroxyethyl cellulose in an amount of from about 1.6 wt% to about 1.9 wt %, and optionally one or more of: a solubilizingagent, a diluent, a pH adjuster, a chelating agent, a preservative, afragrance, and a coloring agent.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of an active agent orpharmaceutically acceptable salt thereof, in an amount of from about0.01 wt % to about 2.0 wt %, propylene glycol in an amount of from about19 wt % to about 21 wt %, ethanol in an amount of from about 18 wt % toabout 20 wt %, hydroxyethyl cellulose in an amount of from about 1.6 wt% to about 1.9 wt %, Polysorbate 20 in an amount of from about 4.5 wt %to about 5.5 wt %, water, and optionally one or more of: a pH adjuster,a chelating agent, a preservative, a fragrance, and a coloring agent.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of an active agent orpharmaceutically acceptable salt thereof, in an amount of from about0.01 wt % to about 2.0 wt %, propylene glycol in an amount of from about19.5 wt % to about 20.5 wt %, ethanol in an amount of from about 18.5 wt% to about 19.5 wt %, hydroxyethyl cellulose in an amount of from about1.7 wt % to about 1.8 wt %, Polysorbate 20 in an amount of from about4.75 wt % to about 5.25 wt %, and optionally one or more of: a diluent,a pH adjuster, a chelating agent, a preservative, a fragrance, and acoloring agent.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of an active agent orpharmaceutically acceptable salt thereof, in an amount of from about0.01wt % to about 2.0 wt %, propylene glycol in an amount of from about19.5 wt % to about 20.5 wt %, ethanol in an amount of from about 18.5 wt% to about 19.5 wt %, hydroxyethyl cellulose in an amount of from about1.7 wt % to about 1.8 wt %, Polysorbate 20 in an amount of from about4.75 wt % to about 5.25 wt %, water, and optionally one or more of: a pHadjuster, a chelating agent, a preservative, a fragrance, and a coloringagent.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of an active agent orpharmaceutically acceptable salt thereof in an amount of from about 0.01wt % to about 2.0 wt %, 20 wt % propylene glycol, 19 wt % ethanol, 1.75wt % hydroxyethyl cellulose, 5 wt % Polysorbate 20, water, andoptionally one or more of: a pH adjuster, a chelating agent, apreservative, a fragrance, and a coloring agent.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of an active agent orpharmaceutically acceptable salt thereof in an amount of from about 0.01wt % to about 2.0 wt %, about 20 wt % propylene glycol, about 19 wt %ethanol, about 1.75 wt % hydroxyethyl cellulose, about 5 wt %Polysorbate 20, water, trolamine, ethylenediaminetetracetic acid (EDTA)or a salt thereof, benzyl alcohol, and optionally one or more of: afragrance, and a coloring agent.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of an active agent orpharmaceutically acceptable salt thereof in an amount of from about 0.01wt % to about 2.0 wt %, about 20 wt % propylene glycol, about 19 wt %ethanol, about 5 wt % Polysorbate 20, about 1.75 wt % hydroxyethylcellulose, about 0.17 wt % trolamine, about 0.02 wt %ethylenediaminetetracetic acid (EDTA) or a salt thereof, about 1 wt %benzyl alcohol, water, and optionally one or more members selected fromthe group consisting of a fragrance and a coloring agent.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of an active agent orpharmaceutically acceptable salt thereof in an amount of from about 0.01wt % to about 1.5 wt %, about 20 wt % propylene glycol, about 19 wt %ethanol, about 5 wt % Polysorbate 20, about 1.75 wt % hydroxyethylcellulose, about 0.17 wt % trolamine, about 0.02 wt %ethylenediaminetetracetic acid (EDTA) or a salt thereof, about 1 wt %benzyl alcohol, and water.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of an active agent orpharmaceutically acceptable salt thereof in an amount of from about 0.01wt % to about 1.0 wt %, about 20 wt % propylene glycol, about 19 wt %ethanol, about 5 wt % Polysorbate 20, about 1.75 wt % hydroxyethylcellulose, about 0.17 wt % trolamine, about 0.02 wt %ethylenediaminetetracetic acid (EDTA) or a salt thereof, about 1 wt %benzyl alcohol, and water.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of an active agent orpharmaceutically acceptable salt thereof in an amount of from about 0.01wt % to about 0.05 wt %, about 20 wt % propylene glycol, about 19 wt %ethanol, about 5 wt % Polysorbate 20, about 1.75 wt % hydroxyethylcellulose, about 0.17 wt % trolamine, about 0.02 wt %ethylenediaminetetracetic acid (EDTA) or a salt thereof, about 1 wt %benzyl alcohol, and water.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of an active agent orpharmaceutically acceptable salt thereof in an amount of from about 0.02wt % to about 0.04 wt %, about 20 wt % propylene glycol, about 19 wt %ethanol, about 5 wt % Polysorbate 20, about 1.75 wt % hydroxyethylcellulose, about 0.17 wt % trolamine, about 0.02 wt %ethylenediaminetetracetic acid (EDTA) or a salt thereof, about 1 wt %benzyl alcohol, and water.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of an active agent orpharmaceutically acceptable salt thereof in an amount of from about 0.02wt % to about 0.03 wt %, about 20 wt % propylene glycol, about 19 wt %ethanol, about 5 wt % Polysorbate 20, about 1.75 wt % hydroxyethylcellulose, 0.17 wt % trolamine, about 0.02 wt %ethylenediaminetetracetic acid (EDTA) or a salt thereof, about 1 wt %benzyl alcohol, and water.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of an active agent orpharmaceutically acceptable salt thereof in an amount of about 0.025 wt%, 20 wt % propylene glycol, about 19 wt % ethanol, about 5 wt %Polysorbate 20, about 1.75 wt % hydroxyethyl cellulose, about 0.17 wt %trolamine, about 0.02 wt % ethylenediaminetetracetic acid (EDTA) or asalt thereof, about 1 wt % benzyl alcohol, and water.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of an active agent orpharmaceutically acceptable salt thereof in an amount of from about 0.03wt % to about 0.07 wt %, about 20 wt % propylene glycol, about 19 wt %ethanol, about 5 wt % Polysorbate 20, about 1.75 wt % hydroxyethylcellulose, about 0.17 wt % trolamine, about 0.02 wt %ethylenediaminetetracetic acid (EDTA) or a salt thereof, about 1 wt %benzyl alcohol, and water.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of an active agent orpharmaceutically acceptable salt thereof in an amount of from about 0.04wt % to about 0.06 wt %, about 20 wt % propylene glycol, about 19 wt %ethanol, about 5 wt % Polysorbate 20, about 1.75 wt % hydroxyethylcellulose, 0.17 wt % trolamine, about 0.02 wt %ethylenediaminetetracetic acid (EDTA) or a salt thereof, about 1 wt %benzyl alcohol, and water.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of an active agent orpharmaceutically acceptable salt thereof in an amount of about 0.05 wt%, 20 wt % propylene glycol, about 19 wt % ethanol, about 5 wt %Polysorbate 20, about 1.75 wt % hydroxyethyl cellulose, about 0.17 wt %trolamine, about 0.02 wt % ethylenediaminetetracetic acid (EDTA) or asalt thereof, about 1 wt % benzyl alcohol, and water.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of an active agent orpharmaceutically acceptable salt thereof in an amount of about 0.025 wt%, 20 wt % propylene glycol, about 19 wt % ethanol, about 5 wt %Polysorbate 20, about 1.75 wt % hydroxyethyl cellulose, about 0.17 wt %trolamine, about 0.02 wt % ethylenediaminetetracetic acid (EDTA) or asalt thereof, about 1 wt % benzyl alcohol, and water.

Gel compositions comprising an antifungal agent

In some embodiments, the present invention provides a gel compositioncomprising or consisting essentially of:

(i) an active agent selected from an antifungal agent;

(ii) a first solvent selected from a glycol solvent;

(iii) a second solvent selected from an alkyl alcohol solvent;

(iv) a non-carbomer rheology modifier selected from a hydroxylcellulose;

(v) a solubolzing agent selected from a polysorbate solubilizing agent;and optionally one or more of: an additional solubilizing agent, adiluent, a preservative, a pH adjuster, a chelating agent, a coloringagent, and a fragrance.

In some embodiments, the present invention provides a gel compositionwherein the active agent is naftifine or a salt thereof. In someembodiments, the present invention provides a gel composition whereinthe active agent is naftifine hydrochloride.

In some embodiments, the present invention provides a gel pharmaceuticalcomposition, comprising or consisting essentially of naftifine orpharmaceutically acceptable salt thereof, in an amount of from about 0.5wt % to about 4.0 wt %, propylene glycol in an amount of about 20 wt %,ethanol in an amount of about 19 wt %, hydroxyethyl cellulose in anamount of about 1.75 wt %, Polysorbate 20 in an amount of about 5 wt %,water, and optionally one or more of: a pH adjuster, a chelating agent,a preservative, a fragrance, and a coloring agent. In certainembodiments, the gel composition is as described above, with theexception that Polysorbate 20 is replaced with Polysorbate 80.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of naftifine or pharmaceuticallyacceptable salt thereof, in an amount of from about 1.0 wt % to about3.0 wt %, about 20 wt % propylene glycol, about 19 wt % ethanol, about1.75 wt % hydroxyethyl cellulose, about 5 wt % Polysorbate 20, water,trolamine, ethylenediaminetetracetic acid (EDTA) or a salt thereof,benzyl alcohol, and optionally one or more of: a fragranceand a coloringagent. In certain embodiments, the gel composition is as describedabove, with the exception that Polysorbate 20 is replaced withPolysorbate 80.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of naftifine or pharmaceuticallyacceptable salt thereof, in an amount of from about 1.0 wt % to about3.0 wt %, about 20 wt % propylene glycol, about 19 wt % ethanol, about1.75 wt % hydroxyethyl cellulose, about 5 wt % Polysorbate 20, water,about 0.17 wt % trolamine, about 0.02 wt % ethylenediaminetetraceticacid (EDTA) or a salt thereof, about 1.0 wt % benzyl alcohol, andoptionally one or more of: a fragrance and a coloring agent. In certainembodiments, the gel composition is as described above, with theexception that Polysorbate 20 is replaced with Polysorbate 80.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of naftifine or pharmaceuticallyacceptable salt thereof in an amount of about 0.1 wt %, 0.5 wt %, 1.0 wt%, 1.5 wt %, 2.0 wt %, 2.5 wt %, 3.0 wt %, 3.5 wt % or 4.0 wt %, about20 wt % propylene glycol, about 19 wt % ethanol, about 1.75 wt %hydroxyethyl cellulose, about 5 wt % Polysorbate 20, water, about 0.17wt % trolamine, about 0.02 wt % ethylenediaminetetracetic acid (EDTA) ora salt thereof, about 1.0 wt % benzyl alcohol, and optionally one ormore of: a fragrance and a coloring agent. In certain embodiments, thegel composition is as described above, with the exception thatPolysorbate 20 is replaced with Polysorbate 80.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of naftifine or pharmaceuticallyacceptable salt thereof in an amount of about 2 wt %, propylene glycolin an amount of about 20 wt %, ethanol in an amount of about 19 wt %,Polysorbate 20 in an amount of about 5 wt %, hydroxyethyl cellulose inan amount of about 1.75 wt %, and water. In certain embodiments, the gelcomposition is as described above, with the exception that Polysorbate20 is replaced with Polysorbate 80.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of naftifine or pharmaceuticallyacceptable salt thereof in an amount of about 2.0 wt %, about 20 wt %propylene glycol, about 19 wt % ethanol, about 1.75 wt % hydroxyethylcellulose, about 5 wt % Polysorbate 20, water, about 0.17 wt %trolamine, about 0.02 wt % ethylenediaminetetracetic acid (EDTA) or asalt thereof, about 1.0 wt % benzyl alcohol, and optionally one or moreof: a fragrance and a coloring agent. In certain embodiments, the gelcomposition is as described above, with the exception that Polysorbate20 is replaced with Polysorbate 80.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of naftifine hydrochloride in anamount of about 2.0 wt %, about 20 wt % propylene glycol, about 19 wt %ethanol, about 1.75 wt % hydroxyethyl cellulose, about 5 wt %Polysorbate 20, water, about 0.17 wt % trolamine, about 0.02 wt %ethylenediaminetetracetic acid (EDTA) or a salt thereof, about 1.0 wt %benzyl alcohol, and optionally one or more of: a fragrance and acoloring agent. In certain embodiments, the gel composition is asdescribed above, with the exception that Polysorbate 20 is replaced withPolysorbate 80.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of naftifine hydrochloride in anamount of about 2.0 wt %, about 20 wt % propylene glycol, about 19 wt %ethanol, about 1.75 wt % hydroxyethyl cellulose, about 5 wt %Polysorbate 20, water, about 0.17 wt % trolamine, about 0.02 wt %ethylenediaminetetracetic acid (EDTA) or a salt thereof, and about 1.0wt % benzyl alcohol. In certain embodiments, the gel composition is asdescribed above, with the exception that Polysorbate 20 is replaced withPolysorbate 80.

In some embodiments, the present invention provides a gel compositionfor topical administration consisting essentially of:

(i) naftifine or a pharmaceutically acceptable salt thereof, present inan amount of from about 0.5 wt % to about 4 wt %;

(ii) a first solvent which is a glycol solvent present in an amount offrom about 10 wt % to about 25 wt %;

(iii) a second solvent which is an alcohol solvent present in an amountof from about 10 wt % to about 25 wt %;

(iv) a non-carbomer rheology modifier; and optionally one or more of: asolubilizing agent, water, a preservative, a pH adjuster, a chelatingagent, a coloring agent, and a fragrance.

In certain embodiments, the gel composition is as described above,wherein the naftifine or a pharmaceutically acceptable salt thereof ispresent in an amount of from about 1.0 wt % to about 3.0 wt %. Incertain embodiments, the gel composition is as described above, whereinthe glycol solvent is present in an amount of about 18 wt % to about 22wt %. In certain embodiments, the gel composition is as described above,wherein the glycol solvent is propylene glycol. In certain embodiments,the gel composition is as described above, wherein the alcohol ispresent in an amount of from about 17 wt % to about 22 wt %. In certainembodiments, the gel composition is as described above, wherein thealcohol is ethanol. In certain embodiments, the gel composition is asdescribed above, wherein the non-carbomer rheology modifier is a hydroxycellulose. In certain embodiments, the gel composition is as describedabove, wherein the hydroxy cellulose is present in an amount of fromabout 0.75 wt % to about 2.25 wt %. In certain embodiments, the gelcomposition is as described above, wherein wherein the hydroxy cellulosehydroxyethyl cellulose. In certain embodiments, the gel composition isas described above, wherein at least one of the one or more solubilizingagents is a polysorbate solubilizing agent. In certain embodiments, thegel composition is as described above, wherein the polysorbatesolubilizing agent is present in an amount of from about 3 wt % to about8 wt %. In certain embodiments, the gel composition is as describedabove, wherein the polysorbate solubilizing agent is Polysorbate 20 orPolysorbate 80. In certain embodiments, the gel composition is asdescribed above, wherein the naftifine or pharmaceutically acceptablesalt thereof is naftifine hydrochloride. In certain embodiments, the gelcomposition is as described above, wherein the naftifine or apharmaceutically acceptable salt thereof (e.g., naftifine hydrochloride)is present in an amount of about 2.0 wt %, the glycol solvent (e.g.,propylene glycol) is present in an amount of about 20 wt %, the alcoholsolvent (e.g., ethanol) is present in an amount of about 19 wt %, thenon-carbomer rheology modifier (e.g., hydroxyethyl cellulose) is presentin an amount of about 1.75 wt %, and the solubilizing agent is apolysorbate (e.g., Polysorbate 20 or Polysorbate 80) present in anamount of about 5 wt %.

In some embodiments, the present invention provides a gel compositioncomprising or consisting essentially of from about 0.01 wt % to about4.0 wt % naftifine, or a pharmaceutically acceptable salt thereof, notmore than 50 wt % of a first solvent, a non-carbomer rheology modifier,a first solubilizing agent, and optionally one or more of: a diluent, apreservative, a pH adjuster, a chelating agent, a coloring agent, and afragrance.

In some embodiments, the present invention provides a gel compositioncomprising or consisting essentially of from about 0.01 wt % to about4.0 wt % naftifine, or a pharmaceutically acceptable salt thereof, notmore than 45 wt % of a first solvent, a non-carbomer rheology modifier,a first solubilizing agent, and optionally one or more of: a diluent, apreservative, a pH adjuster, a chelating agent, a coloring agent, and afragrance.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of from about 0.01 wt % to about4.0 wt % naftifine or a pharmaceutically acceptable salt thereof, notmore than 45 wt % of a first solvent, from about 0.75 wt % to about 2.25wt % of a non-carbomer rheology modifier, from about 1 wt % to less thanabout 10 wt % of a first solubilizing agent, and optionally one or moreof: a diluent, a pH adjuster, a chelating agent, a preservative, afragrance, and a coloring agent.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of from about 0.01 wt % to about4.0 wt % naftifine, or a pharmaceutically acceptable salt thereof, notmore than 45 wt % of an alcohol solvent, from about 0.75 wt % to about2.25 wt % of a hydroxy cellulose, from about 1 wt % to less than about10 wt % of a first solubilizing agent, and optionally one or more of: adiluent, a pH adjuster, a chelating agent, a preservative, a fragrance,and a coloring agent.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of from about 0.01 wt % to about4.0 wt % naftifine, or a pharmaceutically acceptable salt thereof, notmore than 45 wt % of an alcohol solvent, from about 0.75 wt % to about2.25 wt % of a hydroxy cellulose, from about 3 wt % to about 8 wt % of apolysorbate solubilizing agent, and optionally one or more of: adiluent, a pH adjuster, a chelating agent, a preservative, a fragrance,and a coloring agent.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of from about 0.01 wt % to about4.0 wt % naftifine, or a pharmaceutically acceptable salt thereof, notmore than 45 wt % of an alcohol solvent, from about 0.75 wt % to about2.25 wt % of a hydroxy cellulose, from about 3 wt % to about 8 wt %Polysorbate 80, and optionally one or more of: a diluent, a pH adjuster,a chelating agent, a preservative, a fragrance, and a coloring agent.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of from about 0.01 wt % to about4.0 wt % naftifine, or a pharmaceutically acceptable salt thereof, notmore than 45 wt % ethanol, from about 1.25 wt % to about 1.75 wt % ofhydroxy propylcellulose, from about 4 wt % to about 6 wt % Polysorbate80, and optionally one or more of: a diluent, a pH adjuster, a chelatingagent, a preservative, a fragrance, and a coloring agent.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of from about 0.5 wt % to about 3.0wt % naftifine, or a pharmaceutically acceptable salt thereof, not morethan 45 wt % ethanol, from about 1.25 wt % to about 1.75 wt % of hydroxypropylcellulose, from about 4 wt % to about 6 wt % Polysorbate 80, andoptionally one or more of: a diluent, a pH adjuster, a chelating agent,a preservative, a fragrance, and a coloring agent.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of from about 1.0 wt % to about 3.0wt % naftifine, or a pharmaceutically acceptable salt thereof, not morethan 45 wt % ethanol, from about 1.25 wt % to about 1.75 wt % of hydroxypropylcellulose, from about 4 wt % to about 6 wt % Polysorbate 80, andoptionally one or more of: a diluent, a pH adjuster, a chelating agent,a preservative, a fragrance, and a coloring agent.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of from about 1.5 wt % to about 2.5wt % naftifine, or a pharmaceutically acceptable salt thereof, not morethan 45 wt % ethanol, from about 1.25 wt % to about 1.75 wt % of hydroxypropylcellulose, from about 4 wt % to about 6 wt % Polysorbate 80, andoptionally one or more of: a diluent, a pH adjuster, a chelating agent,a preservative, a fragrance, and a coloring agent.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of about 2.0 wt % naftifine, or apharmaceutically acceptable salt thereof, not more than 45 wt % ethanol,about 1.5 wt % of hydroxy propylcellulose, about 5 wt % Polysorbate 80,water, diisopropanolamine, ethylenediaminetetracetic acid (EDTA) or asalt thereof, and optionally one or more of: a fragranceand a coloringagent.

In some embodiments, the present invention provides a gel composition,consisting essentially of from about 2.0 wt % naftifine, or apharmaceutically acceptable salt thereof, about 45 wt % ethanol, about1.5 wt % of hydroxy propylcellulose, about 5 wt % Polysorbate 80, water,about 0.13 wt % diisopropanolamine, about 0.02 wt %ethylenediaminetetracetic acid (EDTA) or a salt thereof, and optionallyone or more of: a fragrance and a coloring agent

Gel Compositions Comprising a Steroidal Anti-Inflammatory Agent

As described above and herein, in some embodiments, the presentinvention provides gel compositions in which the active agent is asteroid. In certain embodiments, the active agent is a corticosteroidsuch as fluticasone (e.g., fluticasone propionate).

Steroids/Fluticasone

As described above and herein, in some embodiments, the presentinvention provides gel compositions comprising or consisting essentiallyof:

(i) an active agent selected from a steroid;

(ii) a first solvent selected from a glycol solvent;

(iii) optionally a second solvent;

(iv) a non-carbomer rheology modifier;

(v) a first solubilizing agent selected from a polysorbate solubilizingagent;

(vi) optionally a second solubilizing agent;

(vii) optionally a third solubilizing agent; and optionally one or moreof: a diluent, a preservative, a pH adjuster, a chelating agent, acoloring agent, and a fragrance. Exemplary such active agents, solvents,non-carbomer rheology modifiers, solubilizing agents,diluents,preservatives, pH adjusters, and chelating agents, aredescribed above and herein. Exemplary such gel compositions aredescribed in further detail below and herein.

In some embodiments, provided gel compositions contain no alkyl alcohol.In certain embodiments, provided gel compositions contain no ethylalcohol.

In some embodiments, the present invention provides a gel compositioncomprising or consisting essentially of at least about 0.01 wt % of asteroid or a pharmaceutically acceptable salt thereof, not more than 50wt % of a first solvent, a non-carbomer rheology modifier, a firstsolubilizing agent, and optionally one or more of: a diluent, apreservative, a pH adjuster, a chelating agent, a coloring agent, and afragrance.

In some embodiments, the present invention provides a gel compositioncomprising or consisting essentially of at least about 0.01 wt % of asteroid or a pharmaceutically acceptable salt thereof, not more than 45wt % of a first solvent, a non-carbomer rheology modifier, a firstsolubilizing agent, and optionally one or more of: a diluent, apreservative, a pH adjuster, a chelating agent, a coloring agent, and afragrance.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of at least about 0.01 wt % of asteroid or a pharmaceutically acceptable salt thereof, not more than 45wt % of a first solvent, from about 0.75 wt % to about 2.25 wt % of anon-carbomer rheology modifier, from about 1 wt % to less than about 10wt % of a first solubilizing agent, and optionally one or more of: adiluent, a pH adjuster, a chelating agent, a preservative, a fragrance,and a coloring agent.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of from about 0.01 wt % to about6.0 wt % of a steroid or a pharmaceutically acceptable salt thereof, notmore than 45 wt % of a first solvent, from about 0.75 wt % to about 2.25wt % of a non-carbomer rheology modifier, from about 1 wt % to less thanabout 10 wt % of a first solubilizing agent, and optionally one or moreof: a diluent, a pH adjuster, a chelating agent, a preservative, afragrance, and a coloring agent.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of from about 0.01 wt % to about4.0 wt % of a steroid or a pharmaceutically acceptable salt thereof, notmore than 45 wt % of a first solvent, from about 0.75 wt % to about 2.25wt % of a non-carbomer rheology modifier, from about 1 wt % to less thanabout 10 wt % of a first solubilizing agent, and optionally one or moreof: a diluent, a pH adjuster, a chelating agent, a preservative, afragrance, and a coloring agent.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of from about 0.01 wt % to about4.0 wt % of a steroid or a pharmaceutically acceptable salt thereof, notmore than 40 wt % of a first solvent, from about 0.75 wt % to about 2.25wt % of a non-carbomer rheology modifier, from about 1 wt % to less thanabout 10 wt % of a first solubilizing agent, and optionally one or moreof: a diluent, a pH adjuster, a chelating agent, a preservative, afragrance, and a coloring agent.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of from about 0.01 wt % to about4.0 wt % of a steroid or a pharmaceutically acceptable salt thereof, notmore than 35 wt % of a first solvent, from about 0.75 wt % to about 2.25wt % of a non-carbomer rheology modifier, from about 1 wt % to less thanabout 10 wt % of a first solubilizing agent, and optionally one or moreof: a diluent, a pH adjuster, a chelating agent, a preservative, afragrance, and a coloring agent.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of from about 0.01 wt % to about4.0 wt % of a steroid or a pharmaceutically acceptable salt thereof, notmore than 30 wt % of a first solvent, from about 0.75 wt % to about 2.25wt % of a non-carbomer rheology modifier, from about 1 wt % to less thanabout 10 wt % of a first solubilizing agent, and optionally one or moreof: a diluent, a pH adjuster, a chelating agent, a preservative, afragrance, and a coloring agent.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of from about 0.01 wt % to about4.0 wt % of a steroid or a pharmaceutically acceptable salt thereof, notmore than 25 wt % of a first solvent, from about 0.75 wt % to about 2.25wt % of a non-carbomer rheology modifier, from about 1 wt % to less thanabout 10 wt % of a first solubilizing agent, and optionally one or moreof: a diluent, a pH adjuster, a chelating agent, a preservative, afragrance, and a coloring agent.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of from about 0.01 wt % to about4.0 wt % of a steroid or a pharmaceutically acceptable salt thereof, notmore than 20 wt % of a first solvent, from about 0.75 wt % to about 2.25wt % of a non-carbomer rheology modifier, from about 1 wt % to less thanabout 10 wt % of a first solubilizing agent, and optionally one or moreof: a diluent, a pH adjuster, a chelating agent, a preservative, afragrance, and a coloring agent.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of from about 0.01 wt % to about4.0 wt % of a steroid or a pharmaceutically acceptable salt thereof,about 30 wt % to about 50 wt % of a glycol solvent, from about 0.75 wt %to about 2.25 wt % of a hydroxy cellulose, from about 1 wt % to lessthan about 10 wt % of a first solubilizing agent, and optionally one ormore of: a diluent, a pH adjuster, a chelating agent, a preservative, afragrance, and a coloring agent.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of from about 0.01 wt % to about4.0 wt % of a steroid or a pharmaceutically acceptable salt thereof,about 30 wt % to about 50 wt % of a glycol solvent, from about 0.75 wt %to about 2.25 wt % of a hydroxy cellulose, from about 3 wt % to about 8wt % of a polysorbate solubilizing agent, and optionally one or more of:a diluent, a pH adjuster, a chelating agent, a preservative, afragrance, and a coloring agent.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of from about 0.01 wt % to about4.0 wt % of a steroid or a pharmaceutically acceptable salt thereof,about 30 wt % to about 50 wt % of a glycol solvent, from about 0.75 wt %to about 2.25 wt % of a hydroxy cellulose, from about 3 wt % to about 8wt % Polysorbate 20, and optionally one or more of: a diluent, a pHadjuster, a chelating agent, a preservative, a fragrance, and a coloringagent.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of from about 0.01 wt % to about4.0 wt % of a steroid or a pharmaceutically acceptable salt thereof,about 35 wt % to about 45 wt % propylene glycol, from about 1.5 wt % toabout 2.0 wt % of hydroxyethyl cellulose, from about 4 wt % to about 6wt % Polysorbate 20, and optionally one or more of: a diluent, a pHadjuster, a chelating agent, a preservative, a fragrance, and a coloringagent.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of from about 0.01 wt % to about1.0 wt % of a steroid or a pharmaceutically acceptable salt thereof,about 35 wt % to about 45 wt % propylene glycol, from about 1.5 wt % toabout 2.0 wt % of hydroxyethyl cellulose, from about 4 wt % to about 6wt % Polysorbate 20, and optionally one or more of: a diluent, a pHadjuster, a chelating agent, a preservative, a fragrance, and a coloringagent.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of from about 0.01 wt % to about0.05 wt % of a steroid or a pharmaceutically acceptable salt thereof,about 35 wt % to about 45 wt % propylene glycol, from about 1.5 wt % toabout 2.0 wt % of hydroxyethyl cellulose, from about 4 wt % to about 6wt % Polysorbate 20, and optionally one or more of: a diluent, a pHadjuster, a chelating agent, a preservative, a fragrance, and a coloringagent.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of about 0.025 wt % of a steroid ora pharmaceutically acceptable salt thereof, about 41 wt % propyleneglycol, about 1.75 wt % of hydroxyethyl cellulose, about 5 wt %Polysorbate 20, water, and optionally one or more of: a pH adjuster, achelating agent, a preservative, a fragrance, and a coloring agent.

In some embodiments, the present invention provides a gel composition,consisting of about 0.025 wt % of a steroid or a pharmaceuticallyacceptable salt thereof, about 41 wt % propylene glycol, about 1.75 wt %of hydroxyethyl cellulose, about 5 wt % Polysorbate 20, water,trolamine, ethylenediaminetetracetic acid (EDTA) or a salt thereof,benzyl alcohol, and optionally one or more of: a fragranceand a coloringagent.

In some embodiments, the present invention provides a gel composition,consisting of about 0.025 wt % of a steroid or a pharmaceuticallyacceptable salt thereof, about 41 wt % propylene glycol, about 1.75 wt %of hydroxyethyl cellulose, about 5 wt % Polysorbate 20, water, about0.17 wt % trolamine, about 0.02 wt % ethylenediaminetetracetic acid(EDTA) or a salt thereof, about 1.0 wt % benzyl alcohol, and optionallyone or more of: a fragranceand a coloring agent.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of from about 0.03 wt % to about0.07 wt % of a steroid or a pharmaceutically acceptable salt thereof,about 35 wt % to about 45 wt % propylene glycol, from about 1.5 wt % toabout 2.0 wt % of hydroxyethyl cellulose, from about 4 wt % to about 6wt % Polysorbate 20, and optionally one or more of: a diluent, a pHadjuster, a chelating agent, a preservative, a fragrance, and a coloringagent.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of about 0.05 wt % of a steroid ora pharmaceutically acceptable salt thereof, about 41 wt % propyleneglycol, about 1.75 wt % of hydroxyethyl cellulose, about 5 wt %Polysorbate 20, water, and optionally one or more of: a pH adjuster, achelating agent, a preservative, a fragrance, and a coloring agent.

In some embodiments, the present invention provides a gel composition,consisting of about 0.05 wt % of a steroid or a pharmaceuticallyacceptable salt thereof, about 41 wt % propylene glycol, about 1.75 wt %of hydroxyethyl cellulose, about 5 wt % Polysorbate 20, water,trolamine, ethylenediaminetetracetic acid (EDTA) or a salt thereof,benzyl alcohol, and optionally one or more of: a fragranceand a coloringagent.

In some embodiments, the present invention provides a gel composition,consisting of about 0.05 wt % of a steroid or a pharmaceuticallyacceptable salt thereof, about 41 wt % propylene glycol, about 1.75 wt %of hydroxyethyl cellulose, about 5 wt % Polysorbate 20, water, about0.17 wt % trolamine, about 0.02 wt % ethylenediaminetetracetic acid(EDTA) or a salt thereof, about 1.0 wt % benzyl alcohol, and optionallyone or more of: a fragranceand a coloring agent.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of from about 0.01 wt % to about4.0 wt % of a steroid or a pharmaceutically acceptable salt thereof,about 15 wt % to about 25 wt % of a glycol solvent, from about 0.75 wt %to about 2.25 wt % of a hydroxy cellulose, from about 3 wt % to about 8wt % of a polysorbate solubilizing agent, and optionally one or more of:a diluent, a pH adjuster, a chelating agent, a preservative, afragrance, and a coloring agent.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of from about 0.01 wt % to about4.0 wt % of a steroid or a pharmaceutically acceptable salt thereof,about 15 wt % to about 25 wt % of a glycol solvent, from about 0.75 wt %to about 2.25 wt % of a hydroxy cellulose, from about 3 wt % to about 8wt % Polysorbate 20, and optionally one or more of: a diluent, a pHadjuster, a chelating agent, a preservative, a fragrance, and a coloringagent.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of from about 0.01 wt % to about4.0 wt % of a steroid or a pharmaceutically acceptable salt thereof,about 18 wt % to about 22 wt % propylene glycol, from about 1.5 wt % toabout 2.0 wt % of hydroxyethyl cellulose, from about 4 wt % to about 6wt % Polysorbate 20, and optionally one or more of: a diluent, a pHadjuster, a chelating agent, a preservative, a fragrance, and a coloringagent.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of from about 0.01 wt % to about1.0 wt % of a steroid or a pharmaceutically acceptable salt thereof,about 18 wt % to about 22 wt % propylene glycol, from about 1.5 wt % toabout 2.0 wt % of hydroxyethyl cellulose, from about 4 wt % to about 6wt % Polysorbate 20, and optionally one or more of: a diluent, a pHadjuster, a chelating agent, a preservative, a fragrance, and a coloringagent.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of from about 0.01 wt % to about0.05 wt % of a steroid or a pharmaceutically acceptable salt thereof,about 18 wt % to about 22 wt % propylene glycol, from about 1.5 wt % toabout 2.0 wt % of hydroxyethyl cellulose, from about 4 wt % to about 6wt % Polysorbate 20, and optionally one or more of: a diluent, a pHadjuster, a chelating agent, a preservative, a fragrance, and a coloringagent.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of about 0.025 wt % of a steroid ora pharmaceutically acceptable salt thereof, about 20 wt % propyleneglycol, about 1.75 wt % of hydroxyethyl cellulose, about 5 wt %Polysorbate 20, water, and optionally one or more of: a pH adjuster, achelating agent, a preservative, a fragrance, and a coloring agent.

In some embodiments, the present invention provides a gel composition,consisting of about 0.025 wt % of a steroid or a pharmaceuticallyacceptable salt thereof, about 20 wt % propylene glycol, about 1.75 wt %of hydroxyethyl cellulose, about 5 wt % Polysorbate 20, water,ethylenediaminetetracetic acid (EDTA) or a salt thereof, and optionallyone or more of: a preservative, a pH adjuster, a fragrance and acoloring agent.

In some embodiments, the present invention provides a gel composition,consisting of about 0.025 wt % of a steroid or a pharmaceuticallyacceptable salt thereof, about 20 wt % propylene glycol, about 1.75 wt %of hydroxyethyl cellulose, about 5 wt % Polysorbate 20, water, about0.02 wt % ethylenediaminetetracetic acid (EDTA) or a salt thereof, andoptionally one or more of: preservative, a pH adjuster, a fragrance anda coloring agent.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of from about 0.03 wt % to about0.07 wt % of a steroid or a pharmaceutically acceptable salt thereof,about 35 wt % to about 45 wt % propylene glycol, from about 1.5 wt % toabout 2.0 wt % of hydroxyethyl cellulose, from about 4 wt % to about 6wt % Polysorbate 20, and optionally one or more of: a diluent, a pHadjuster, a chelating agent, a preservative, a fragrance, and a coloringagent.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of about 0.05 wt % of a steroid ora pharmaceutically acceptable salt thereof, about 20 wt % propyleneglycol, about 1.75 wt % of hydroxyethyl cellulose, about 5 wt %Polysorbate 20, water, and optionally one or more of: a pH adjuster, achelating agent, a preservative, a fragrance, and a coloring agent.

In some embodiments, the present invention provides a gel composition,consisting of about 0.05 wt % of a steroid or a pharmaceuticallyacceptable salt thereof, about 20 wt % propylene glycol, about 1.75 wt %of hydroxyethyl cellulose, about 5 wt % Polysorbate 20, water,ethylenediaminetetracetic acid (EDTA) or a salt thereof, and optionallyone or more of: preservative, a pH adjuster, a fragrance and a coloringagent.

In some embodiments, the present invention provides a gel composition,consisting of about 0.05 wt % of a steroid or a pharmaceuticallyacceptable salt thereof, about 20 wt % propylene glycol, about 1.75 wt %of hydroxyethyl cellulose, about 5 wt % Polysorbate 20, water, about0.02 wt % ethylenediaminetetracetic acid (EDTA) or a salt thereof, andoptionally one or more of: preservative, a pH adjuster, a fragrance anda coloring agent.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of from about 0.01 wt % to about3.0 wt % of a steroid, or a pharmaceutically acceptable salt thereof,from about 10 wt % to about 30 wt % of a first solvent, from about 0.75wt % to about 2.25 wt % of a non-carbomer rheology modifier, from about1 wt % to less than about 10 wt % of a first solubilizing agent, fromabout 1 wt % to less than about 10 wt % of a second solubilizing agent,optionally a third solubilizing agent, and optionally one or more of: adiluent, a pH adjuster, a chelating agent, a preservative, a fragrance,and a coloring agent.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of from about 0.01 wt % to about3.0 wt % of a steroid, or a pharmaceutically acceptable salt thereof,from about 15 wt % to about 25 wt % of a first solvent, from about 0.75wt % to about 2.25 wt % of a non-carbomer rheology modifier, from about1 wt % to less than about 10 wt % of a first solubilizing agent, fromabout 1 wt % to less than about 10 wt % of a second solubilizing agent,optionally a third solubilizing agent, and optionally one or more of: adiluent, a pH adjuster, a chelating agent, a preservative, a fragrance,and a coloring agent.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of from about 0.01 wt % to about2.0 wt % of a steroid, or a pharmaceutically acceptable salt thereof,from about 15 wt % to about 25 wt % of a first solvent, from about 0.75wt % to about 2.25 wt % of a non-carbomer rheology modifier, from about1 wt % to less than about 10 wt % of a first solubilizing agent, fromabout 1 wt % to less than about 10 wt % of a second solubilizingagent,optionally a third solubilizing agent, and optionally one or moreof: a diluent, a pH adjuster, a chelating agent, a preservative, afragrance, and a coloring agent.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of from about 0.01 wt % to about2.0 wt % of a steroid, or a pharmaceutically acceptable salt thereof,from about 15 wt % to about 25 wt % of a glycol solvent, from about 0.75wt % to about 2.25 wt % of a hydroxyl cellulose, from about 1 wt % toless than about 10 wt % of a polysorbate solubilizing agent, from about1 wt % to less than about 10 wt % of a second solubilizing agent,optionally a third solubilizing agent, and optionally one or more of: adiluent, a pH adjuster, a chelating agent, a preservative, a fragrance,and a coloring agent.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of from about 0.01 wt % to about2.0 wt % of a steroid, or a pharmaceutically acceptable salt thereof,from about 15 wt % to about 25 wt % of a glycol solvent, from about 0.75wt % to about 2.25 wt % of a hydroxy cellulose, from about 3 wt % toabout 8 wt % of a polysorbate solubilizing agent, a second solubilizingagent, optionally a third solubilizing agent, and optionally one or moreof: a diluent, a pH adjuster, a chelating agent, a preservative, afragrance, and a coloring agent. In certain embodiments, the gelcomposition is as described above, and the optional third solubilizingagent is absent. In certain embodiments, the gel composition is asdescribed above, and the optional third solubilizing agent is present.In certain embodiments, the gel composition is as described above, andeither the second or third solubilizing agent is an alcohol solubilizingagent. In certain embodiments, the alcohol solubilizing reagent ispresent in an amount ranging from about 1 wt % to about 9 wt %. Incertain embodiments, the alcohol solubilizing agent is present in anamount ranging from about 2 wt % to about 8 wt %. In certainembodiments, the alcohol solubilizing agent is present in an amount ofabout 3 wt % to about 6 wt %. In certain embodiments, the alcoholsolubilizing agent is present in an amount of less than about 1 wt %. Incertain embodiments, the alcohol solubilizing agent is present in anamount of about 1 wt %. In certain embodiments, the alcohol solubilizingagent is present in an amount of about 1.5 wt %. In certain embodiments,the alcohol solubilizing agent is present in an amount of about 2 wt %.In certain embodiments, the alcohol solubilizing agent is present in anamount of about 2.5 wt %. In certain embodiments, the alcoholsolubilizing agent is present in an amount of about 3 wt %. In certainembodiments, the alcohol solubilizing agent is present in an amount ofabout 3.5 wt %. In certain embodiments, the alcohol solubilizing agentis present in an amount of about 4 wt %. In certain embodiments, thealcohol solubilizing agent is present in an amount of about 4.5 wt %. Incertain embodiments, the alcohol solubilizing agent is present in anamount of about 5 wt %. In certain embodiments, the alcohol solubilizingagent is present in an amount of about 5.5 wt %. In certain embodiments,the alcohol solubilizing agent is present in an amount of about 6 wt %.In certain embodiments, the alcohol solubilizing agent is present in anamount of about 6.5 wt %. In certain embodiments, the alcoholsolubilizing agent is present in an amount of about 7 wt %. In certainembodiments, the alcohol solubilizing agent is present in an amount ofabout 7.5 wt %. In certain embodiments, the alcohol solubilizing agentis present in an amount of about 8 wt %. In certain embodiments, thealcohol solubilizing agent is present in an amount of about 8.5 wt %. Incertain embodiments, the alcohol solubilizing agent is present in anamount of about 9 wt %. In certain embodiments, the alcohol solubilizingagent is present in an amount of about 9.5 wt %. Exemplary such alcoholsolubilizing agents are described above and herein and include, e.g.,methanol, ethanol, propanol, and the like. In certain embodiments, thegel composition is as described above, and either the second or thirdsolubilizing agent is a glycol ether solubilizing agent. In certainembodiments, the glycol ether solubilizing reagent is present in anamount ranging from about 1 wt % to about 9 wt %. In certainembodiments, the glycol ether solubilizing agent is present in an amountranging from about 1 wt % to about 5 wt %. In certain embodiments, theglycol ether solubilizing agent is present in an amount of about 1 wt %to about 3 wt %. In certain embodiments, the glycol ether solubilizingagent is present in an amount of less than about 1 wt %. In certainembodiments, the glycol ether solubilizing agent is present in an amountof about 1 wt %. In certain embodiments, the glycol ether solubilizingagent is present in an amount of about 1.1 wt %. In certain embodiments,the glycol ether solubilizing agent is present in an amount of about 1.2wt %. In certain embodiments, the glycol ether solubilizing agent ispresent in an amount of about 1.3 wt %. In certain embodiments, theglycol ether solubilizing agent is present in an amount of about 1.4 wt%. In certain embodiments, the glycol ether solubilizing agent ispresent in an amount of about 1.5 wt %. In certain embodiments, theglycol ether solubilizing agent is present in an amount of about 1.6 wt%. In certain embodiments, the glycol ether solubilizing agent ispresent in an amount of about 1.7 wt %. In certain embodiments, theglycol ether solubilizing agent is present in an amount of about 1.8 wt%. In certain embodiments, the glycol ether solubilizing agent ispresent in an amount of about 1.9 wt %. In certain embodiments, theglycol ether solubilizing agent is present in an amount of about 2.0 wt%. Exemplary such glycol ether solubilizing agents are described aboveand herein and include dialkylene glycol monoalkylethers such as, e.g.,diethylene glycol monoethylether.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of from about 0.01 wt % to about2.0 wt % fluticasone, or a pharmaceutically acceptable salt thereof,from about 15 wt % to about 25 wt % propylene glycol, from about 0.75 wt% to about 2.25 wt % of hydroxyethyl cellulose, from about 3 wt % toabout 8 wt % of Polysorbate 20, a second solubilizing agent, optionallya third solubilizing agent, and optionally one or more of: a diluent, apH adjuster, a chelating agent, a preservative, a fragrance, and acoloring agent. In certain embodiments, the gel composition is asdescribed above, and the optional third solubilizing agent is absent. Incertain embodiments, the gel composition is as described above, and theoptional third solubilizing agent is present. In certain embodiments,the gel composition is as described above, and either the second orthird solubilizing agent is an alcohol solubilizing agent. In certainembodiments, the alcohol solubilizing reagent is present in an amountranging from about 1 wt % to about 9 wt %. In certain embodiments, thealcohol solubilizing agent is present in an amount ranging from about 2wt % to about 8 wt %. In certain embodiments, the alcohol solubilizingagent is present in an amount of about 3 wt % to about 6 wt %. Incertain embodiments, the alcohol solubilizing agent is present in anamount of less than about 1 wt %. In certain embodiments, the alcoholsolubilizing agent is present in an amount of about 1 wt %. In certainembodiments, the alcohol solubilizing agent is present in an amount ofabout 1.5 wt %. In certain embodiments, the alcohol solubilizing agentis present in an amount of about 2 wt %. In certain embodiments, thealcohol solubilizing agent is present in an amount of about 2.5 wt %. Incertain embodiments, the alcohol solubilizing agent is present in anamount of about 3 wt %. In certain embodiments, the alcohol solubilizingagent is present in an amount of about 3.5 wt %. In certain embodiments,the alcohol solubilizing agent is present in an amount of about 4 wt %.In certain embodiments, the alcohol solubilizing agent is present in anamount of about 4.5 wt %. In certain embodiments, the alcoholsolubilizing agent is present in an amount of about 5 wt %. In certainembodiments, the alcohol solubilizing agent is present in an amount ofabout 5.5 wt %. In certain embodiments, the alcohol solubilizing agentis present in an amount of about 6 wt %. In certain embodiments, thealcohol solubilizing agent is present in an amount of about 6.5 wt %. Incertain embodiments, the alcohol solubilizing agent is present in anamount of about 7 wt %. In certain embodiments, the alcohol solubilizingagent is present in an amount of about 7.5 wt %. In certain embodiments,the alcohol solubilizing agent is present in an amount of about 8 wt %.In certain embodiments, the alcohol solubilizing agent is present in anamount of about 8.5 wt %. In certain embodiments, the alcoholsolubilizing agent is present in an amount of about 9 wt %. In certainembodiments, the alcohol solubilizing agent is present in an amount ofabout 9.5 wt %. Exemplary such alcohol solubilizing agents are describedabove and herein and include, e.g., methanol, ethanol, propanol, and thelike. In certain embodiments, the gel composition is as described above,and either the second or third solubilizing agent is a glycol ethersolubilizing agent. In certain embodiments, the glycol ethersolubilizing reagent is present in an amount ranging from about 1 wt %to about 9 wt %. In certain embodiments, the glycol ether solubilizingagent is present in an amount ranging from about 1 wt % to about 5 wt %.In certain embodiments, the glycol ether solubilizing agent is presentin an amount of about 1 wt % to about 3 wt %. In certain embodiments,the glycol ether solubilizing agent is present in an amount of less thanabout 1 wt %. In certain embodiments, the glycol ether solubilizingagent is present in an amount of about 1 wt %. In certain embodiments,the glycol ether solubilizing agent is present in an amount of about 1.1wt %. In certain embodiments, the glycol ether solubilizing agent ispresent in an amount of about 1.2 wt %. In certain embodiments, theglycol ether solubilizing agent is present in an amount of about 1.3 wt%. In certain embodiments, the glycol ether solubilizing agent ispresent in an amount of about 1.4 wt %. In certain embodiments, theglycol ether solubilizing agent is present in an amount of about 1.5 wt%. In certain embodiments, the glycol ether solubilizing agent ispresent in an amount of about 1.6 wt %. In certain embodiments, theglycol ether solubilizing agent is present in an amount of about 1.7 wt%. In certain embodiments, the glycol ether solubilizing agent ispresent in an amount of about 1.8 wt %. In certain embodiments, theglycol ether solubilizing agent is present in an amount of about 1.9 wt%. In certain embodiments, the glycol ether solubilizing agent ispresent in an amount of about 2.0 wt %. Exemplary such glycol ethersolubilizing agents are described above and herein and includedialkylene glycol monoalkylethers such as, e.g., diethylene glycolmonoethylether.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of about 0.025 wt % fluticasone, ora pharmaceutically acceptable salt thereof, about 20 wt % propyleneglycol, about 1.75 wt % hydroxyethyl cellulose, about 5 wt % ofPolysorbate 20, a second solubilizing agent, optionally a thirdsolubilizing agent, and optionally one or more of: a diluent, a pHadjuster, a chelating agent, a preservative, a fragrance, and a coloringagent. In certain embodiments, the gel composition is as describedabove, and the optional third solubilizing agent is absent. In certainembodiments, the gel composition is as described above, and the optionalthird solubilizing agent is present. In certain embodiments, the gelcomposition is as described above, and either the second or thirdsolubilizing agent is an alcohol solubilizing agent. In certainembodiments, the alcohol solubilizing reagent is present in an amountranging from about 1 wt % to about 9 wt %. In certain embodiments, thealcohol solubilizing agent is present in an amount ranging from about 2wt % to about 8 wt %. In certain embodiments, the alcohol solubilizingagent is present in an amount of about 3 wt % to about 6 wt %. Incertain embodiments, the alcohol solubilizing agent is present in anamount of less than about 1 wt %. In certain embodiments, the alcoholsolubilizing agent is present in an amount of about 1 wt %. In certainembodiments, the alcohol solubilizing agent is present in an amount ofabout 1.5 wt %. In certain embodiments, the alcohol solubilizing agentis present in an amount of about 2 wt %. In certain embodiments, thealcohol solubilizing agent is present in an amount of about 2.5 wt %. Incertain embodiments, the alcohol solubilizing agent is present in anamount of about 3 wt %. In certain embodiments, the alcohol solubilizingagent is present in an amount of about 3.5 wt %. In certain embodiments,the alcohol solubilizing agent is present in an amount of about 4 wt %.In certain embodiments, the alcohol solubilizing agent is present in anamount of about 4.5 wt %. In certain embodiments, the alcoholsolubilizing agent is present in an amount of about 5 wt %. In certainembodiments, the alcohol solubilizing agent is present in an amount ofabout 5.5 wt %. In certain embodiments, the alcohol solubilizing agentis present in an amount of about 6 wt %. In certain embodiments, thealcohol solubilizing agent is present in an amount of about 6.5 wt %. Incertain embodiments, the alcohol solubilizing agent is present in anamount of about 7 wt %. In certain embodiments, the alcohol solubilizingagent is present in an amount of about 7.5 wt %. In certain embodiments,the alcohol solubilizing agent is present in an amount of about 8 wt %.In certain embodiments, the alcohol solubilizing agent is present in anamount of about 8.5 wt %. In certain embodiments, the alcoholsolubilizing agent is present in an amount of about 9 wt %. In certainembodiments, the alcohol solubilizing agent is present in an amount ofabout 9.5 wt %. Exemplary such alcohol solubilizing agents are describedabove and herein and include, e.g., methanol, ethanol, propanol, and thelike.In certain embodiments, the gel composition is as described above,and either the second or third solubilizing agent is a glycol ethersolubilizing agent. In certain embodiments, the glycol ethersolubilizing reagent is present in an amount ranging from about 1 wt %to about 9 wt %. In certain embodiments, the glycol ether solubilizingagent is present in an amount ranging from about 1 wt % to about 5 wt %.In certain embodiments, the glycol ether solubilizing agent is presentin an amount of about 1 wt % to about 3 wt %. In certain embodiments,the glycol ether solubilizing agent is present in an amount of less thanabout 1 wt %. In certain embodiments, the glycol ether solubilizingagent is present in an amount of about 1 wt %. In certain embodiments,the glycol ether solubilizing agent is present in an amount of about 1.1wt %. In certain embodiments, the glycol ether solubilizing agent ispresent in an amount of about 1.2 wt %. In certain embodiments, theglycol ether solubilizing agent is present in an amount of about 1.3 wt%. In certain embodiments, the glycol ether solubilizing agent ispresent in an amount of about 1.4 wt %. In certain embodiments, theglycol ether solubilizing agent is present in an amount of about 1.5 wt%. In certain embodiments, the glycol ether solubilizing agent ispresent in an amount of about 1.6 wt %. In certain embodiments, theglycol ether solubilizing agent is present in an amount of about 1.7 wt%. In certain embodiments, the glycol ether solubilizing agent ispresent in an amount of about 1.8 wt %. In certain embodiments, theglycol ether solubilizing agent is present in an amount of about 1.9 wt%. In certain embodiments, the glycol ether solubilizing agent ispresent in an amount of about 2.0 wt %. Exemplary such glycol ethersolubilizing agents are described above and herein and includedialkylene glycol monoalkylethers such as, e.g., diethylene glycolmonoethylether.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of from about 0.01 wt % to about2.0 wt % of a steroid, or a pharmaceutically acceptable salt thereof,from about 15 wt % to about 25 wt % of a glycol solvent, from about 0.75wt % to about 2.25 wt % of a hydroxy cellulose, from about 3 wt % toabout 8 wt % of a polysorbate solubilizing agent, from about 1 wt % toless than about 10 wt % of a second solubilizing agent, optionally athird solubilizing agent, and optionally one or more of: a diluent, a pHadjuster, a chelating agent, a preservative, a fragrance, and a coloringagent.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of from about 0.01 wt % to about2.0 wt % of a steroid, or a pharmaceutically acceptable salt thereof,from about 15 wt % to about 25 wt % propylene glycol, from about 0.75 wt% to about 2.25 wt % of hydroxyethyl cellulose, from about 3 wt % toabout 8 wt % of Polysorbate 20, from about 1 wt % to less than about 10wt % of a second solubilizing agent, optionally a third solubilizingagent, and optionally one or more of: a diluent, a pH adjuster, achelating agent, a preservative, a fragrance, and a coloring agent.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of from about 0.01 wt % to about2.0 wt % of a steroid, or a pharmaceutically acceptable salt thereof,from about 15 wt % to about 25 wt % propylene glycol, from about 0.75 wt% to about 2.25 wt % of hydroxyethyl cellulose, from about 3 wt % toabout 8 wt % of Polysorbate 20, from about 1 wt % to less than about 10wt % of a second solubilizing agent selected from an alcohol or glycolether solubilizing agent, optionally from about 1 wt % to less thanabout 10 wt % of a third solubilizing agent, and optionally one or moreof: a diluent, a pH adjuster, a chelating agent, a preservative, afragrance, and a coloring agent.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of from about 0.01 wt % to about2.0 wt % of a steroid, or a pharmaceutically acceptable salt thereof,from about 15 wt % to about 25 wt % propylene glycol, from about 0.75 wt% to about 2.25 wt % of hydroxyethyl cellulose, from about 3 wt % toabout 8 wt % of Polysorbate 20, from about 1 wt % to less than about 10wt % of a second solubilizing agent selected from an alcohol or glycolether solubilizing agent,optionally from about 1 wt % to less than about10 wt % of a third solubilizing agent selected from an alcohol or glycolether solubilizing agent, and optionally one or more of: a diluent, a pHadjuster, a chelating agent, a preservative, a fragrance, and a coloringagent.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of from about 0.01 wt % to about2.0 wt % of a steroid, or a pharmaceutically acceptable salt thereof,from about 15 wt % to about 25 wt % propylene glycol, from about 0.75 wt% to about 2.25 wt % of hydroxyethyl cellulose, from about 3 wt % toabout 8 wt % of Polysorbate 20, from about 7 wt % to about 9 wt % of analcohol solubilizing agent,optionally from about 1 wt % to about 3 wt %of a glycol ether solubilizing agent, and optionally one or more of: adiluent, a pH adjuster, a chelating agent, a preservative, a fragrance,and a coloring agent.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of from about 0.01 wt % to about2.0 wt % of a steroid, or a pharmaceutically acceptable salt thereof,from about 15 wt % to about 25 wt % propylene glycol, from about 0.75 wt% to about 2.25 wt % of hydroxyethyl cellulose, from about 3 wt % toabout 8 wt % of Polysorbate 20, from about 1 wt % to about 3 wt % of aglycol ether solubilizing agent, optionally from about 3 wt % to about 8wt % of an alcohol solubilizing agent selected, and optionally one ormore of: a diluent, a pH adjuster, a chelating agent, a preservative, afragrance, and a coloring agent.

Fluticasone

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of from about 0.01 wt % to about0.1 wt % fluticasone or a pharmaceutically acceptable salt thereof, notmore than 40 wt % of a first solvent, from about 0.75 wt % to about 2.25wt % of a non-carbomer rheology modifier, from about 1 wt % to less thanabout 10 wt % of a first solubilizing agent, and optionally one or moreof: a diluent, a pH adjuster, a chelating agent, a preservative, afragrance, and a coloring agent.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of from about 0.01 wt % to about0.1 wt % fluticasone or a pharmaceutically acceptable salt thereof, notmore than 35 wt % of a first solvent, from about 0.75 wt % to about 2.25wt % of a non-carbomer rheology modifier, from about 1 wt % to less thanabout 10 wt % of a first solubilizing agent, and optionally one or moreof: a diluent, a pH adjuster, a chelating agent, a preservative, afragrance, and a coloring agent.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of from about 0.01 wt % to about0.1 wt % fluticasone or a pharmaceutically acceptable salt thereof, notmore than 30 wt % of a first solvent, from about 0.75 wt % to about 2.25wt % of a non-carbomer rheology modifier, from about 1 wt % to less thanabout 10 wt % of a first solubilizing agent, and optionally one or moreof: a diluent, a pH adjuster, a chelating agent, a preservative, afragrance, and a coloring agent.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of from about 0.01 wt % to about0.1 wt % fluticasone or a pharmaceutically acceptable salt thereof, notmore than 25 wt % of a first solvent, from about 0.75 wt % to about 2.25wt % of a non-carbomer rheology modifier, from about 1 wt % to less thanabout 10 wt % of a first solubilizing agent, and optionally one or moreof: a diluent, a pH adjuster, a chelating agent, a preservative, afragrance, and a coloring agent.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of from about 0.01 wt % to about0.1 wt % fluticasone or a pharmaceutically acceptable salt thereof, notmore than 20 wt % of a first solvent, from about 0.75 wt % to about 2.25wt % of a non-carbomer rheology modifier, from about 1 wt % to less thanabout 10 wt % of a first solubilizing agent, and optionally one or moreof: a diluent, a pH adjuster, a chelating agent, a preservative, afragrance, and a coloring agent.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of from about 0.01 wt % to about0.1 wt % fluticasone or a pharmaceutically acceptable salt thereof,about 30 wt % to about 50 wt % of a glycol solvent, from about 0.75 wt %to about 2.25 wt % of a hydroxy cellulose, from about 1 wt % to lessthan about 10 wt % of a first solubilizing agent, and optionally one ormore of: a diluent, a pH adjuster, a chelating agent, a preservative, afragrance, and a coloring agent.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of from about 0.01 wt % to about0.1 wt % fluticasone or a pharmaceutically acceptable salt thereof,about 30 wt % to about 50 wt % of a glycol solvent, from about 0.75 wt %to about 2.25 wt % of a hydroxy cellulose, from about 3 wt % to about 8wt % of a polysorbate solubilizing agent, and optionally one or more of:a diluent, a pH adjuster, a chelating agent, a preservative, afragrance, and a coloring agent.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of from about 0.01 wt % to about0.1 wt % fluticasone or a pharmaceutically acceptable salt thereof,about 30 wt % to about 50 wt % of a glycol solvent, from about 0.75 wt %to about 2.25 wt % of a hydroxy cellulose, from about 3 wt % to about 8wt % Polysorbate 20, and optionally one or more of: a diluent, a pHadjuster, a chelating agent, a preservative, a fragrance, and a coloringagent.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of from about 0.01 wt % to about0.1 wt % fluticasone or a pharmaceutically acceptable salt thereof,about 35 wt % to about 45 wt % propylene glycol, from about 1.5 wt % toabout 2.0 wt % of hydroxyethyl cellulose, from about 4 wt % to about 6wt % Polysorbate 20, and optionally one or more of: a diluent, a pHadjuster, a chelating agent, a preservative, a fragrance, and a coloringagent.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of from about 0.01 wt % to about0.075 wt % fluticasone or a pharmaceutically acceptable salt thereof,about 35 wt % to about 45 wt % propylene glycol, from about 1.5 wt % toabout 2.0 wt % of hydroxyethyl cellulose, from about 4 wt % to about 6wt % Polysorbate 20, and optionally one or more of: a diluent, a pHadjuster, a chelating agent, a preservative, a fragrance, and a coloringagent.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of from about 0.01 wt % to about0.075 wt % fluticasone or a pharmaceutically acceptable salt thereof,about 35 wt % to about 45 wt % propylene glycol, from about 1.5 wt % toabout 2.0 wt % of hydroxyethyl cellulose, from about 4 wt % to about 6wt % Polysorbate 20, and optionally one or more of: a diluent, a pHadjuster, a chelating agent, a preservative, a fragrance, and a coloringagent.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of about 0.025 wt % fluticasone ora pharmaceutically acceptable salt thereof, about 41 wt % propyleneglycol, about 1.75 wt % of hydroxyethyl cellulose, about 5 wt %Polysorbate 20, water, and optionally one or more of: a pH adjuster, achelating agent, a preservative, a fragrance, and a coloring agent.

In some embodiments, the present invention provides a gel composition,consisting of about 0.025 wt % fluticasone or a pharmaceuticallyacceptable salt thereof, about 41 wt % propylene glycol, about 1.75 wt %of hydroxyethyl cellulose, about 5 wt % Polysorbate 20, water,trolamine, ethylenediaminetetracetic acid (EDTA) or a salt thereof,benzyl alcohol, and optionally one or more of: a fragranceand a coloringagent.

In some embodiments, the present invention provides a gel composition,consisting of about 0.025 wt % fluticasone or a pharmaceuticallyacceptable salt thereof, about 41 wt % propylene glycol, about 1.75 wt %of hydroxyethyl cellulose, about 5 wt % Polysorbate 20, water, about0.17 wt % trolamine, about 0.02 wt % ethylenediaminetetracetic acid(EDTA) or a salt thereof, about 1.0 wt % benzyl alcohol, and optionallyone or more of: a fragranceand a coloring agent.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of from about 0.03 wt % to about0.07 wt % fluticasone or a pharmaceutically acceptable salt thereof,about 35 wt % to about 45 wt % propylene glycol, from about 1.5 wt % toabout 2.0 wt % of hydroxyethyl cellulose, from about 4 wt % to about 6wt % Polysorbate 20, and optionally one or more of: a diluent, a pHadjuster, a chelating agent, a preservative, a fragrance, and a coloringagent.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of about 0.05 wt % fluticasone or apharmaceutically acceptable salt thereof, about 41 wt % propyleneglycol, about 1.75 wt % of hydroxyethyl cellulose, about 5 wt %Polysorbate 20, water, and optionally one or more of: a pH adjuster, achelating agent, a preservative, a fragrance, and a coloring agent.

In some embodiments, the present invention provides a gel composition,consisting of about 0.05 wt % fluticasone or a pharmaceuticallyacceptable salt thereof, about 41 wt % propylene glycol, about 1.75 wt %of hydroxyethyl cellulose, about 5 wt % Polysorbate 20, water,trolamine, ethylenediaminetetracetic acid (EDTA) or a salt thereof,benzyl alcohol, and optionally one or more of: a fragranceand a coloringagent.

In some embodiments, the present invention provides a gel composition,consisting of about 0.05 wt % fluticasone or a pharmaceuticallyacceptable salt thereof, about 41 wt % propylene glycol, about 1.75 wt %of hydroxyethyl cellulose, about 5 wt % Polysorbate 20, water, about0.17 wt % trolamine, about 0.02 wt % ethylenediaminetetracetic acid(EDTA) or a salt thereof, about 1.0 wt % benzyl alcohol, and optionallyone or more of: a fragranceand a coloring agent.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of from about 0.01 wt % to about0.1 wt % fluticasone or a pharmaceutically acceptable salt thereof,about 15 wt % to about 25 wt % of a glycol solvent, from about 0.75 wt %to about 2.25 wt % of a hydroxy cellulose, from about 3 wt % to about 8wt % of a polysorbate solubilizing agent, and optionally one or more of:a diluent, a pH adjuster, a chelating agent, a preservative, afragrance, and a coloring agent.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of from about 0.01 wt % to about0.1 wt % fluticasone or a pharmaceutically acceptable salt thereof,about 15 wt % to about 25 wt % of a glycol solvent, from about 0.75 wt %to about 2.25 wt % of a hydroxy cellulose, from about 3 wt % to about 8wt % Polysorbate 20, and optionally one or more of: a diluent, a pHadjuster, a chelating agent, a preservative, a fragrance, and a coloringagent.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of from about 0.01 wt % to about0.1 wt % fluticasone or a pharmaceutically acceptable salt thereof,about 18 wt % to about 22 wt % propylene glycol, from about 1.5 wt % toabout 2.0 wt % of hydroxyethyl cellulose, from about 4 wt % to about 6wt % Polysorbate 20, and optionally one or more of: a diluent, a pHadjuster, a chelating agent, a preservative, a fragrance, and a coloringagent.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of from about 0.01 wt % to about0.075 wt % fluticasone or a pharmaceutically acceptable salt thereof,about 18 wt % to about 22 wt % propylene glycol, from about 1.5 wt % toabout 2.0 wt % of hydroxyethyl cellulose, from about 4 wt % to about 6wt % Polysorbate 20, and optionally one or more of: a diluent, a pHadjuster, a chelating agent, a preservative, a fragrance, and a coloringagent.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of about 0.025 wt % fluticasone ora pharmaceutically acceptable salt thereof, about 20 wt % propyleneglycol, about 1.75 wt % of hydroxyethyl cellulose, about 5 wt %Polysorbate 20, water, and optionally one or more of: a pH adjuster, achelating agent, a preservative, a fragrance, and a coloring agent.

In some embodiments, the present invention provides a gel composition,consisting of about 0.025 wt % fluticasone or a pharmaceuticallyacceptable salt thereof, about 20 wt % propylene glycol, about 1.75 wt %of hydroxyethyl cellulose, about 5 wt % Polysorbate 20, water,ethylenediaminetetracetic acid (EDTA) or a salt thereof, and optionallyone or more of: a preservative, a pH adjuster, a fragrance and acoloring agent.

In some embodiments, the present invention provides a gel composition,consisting of about 0.025 wt % fluticasone or a pharmaceuticallyacceptable salt thereof, about 20 wt % propylene glycol, about 1.75 wt %of hydroxyethyl cellulose, about 5 wt % Polysorbate 20, water, about0.02 wt % ethylenediaminetetracetic acid (EDTA) or a salt thereof, andoptionally one or more of: preservative, a pH adjuster, a fragrance anda coloring agent.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of from about 0.03 wt % to about0.07 wt % fluticasone or a pharmaceutically acceptable salt thereof,about 35 wt % to about 45 wt % propylene glycol, from about 1.5 wt % toabout 2.0 wt % of hydroxyethyl cellulose, from about 4 wt % to about 6wt %

Polysorbate 20, and optionally one or more of: a diluent, a pH adjuster,a chelating agent, a preservative, a fragrance, and a coloring agent.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of about 0.05 wt % fluticasone or apharmaceutically acceptable salt thereof, about 20 wt % propyleneglycol, about 1.75 wt % of hydroxyethyl cellulose, about 5 wt %Polysorbate 20, water, and optionally one or more of: a pH adjuster, achelating agent, a preservative, a fragrance, and a coloring agent.

In some embodiments, the present invention provides a gel composition,consisting of about 0.05 wt % fluticasone or a pharmaceuticallyacceptable salt thereof, about 20 wt % propylene glycol, about 1.75 wt %of hydroxyethyl cellulose, about 5 wt % Polysorbate 20, water,ethylenediaminetetracetic acid (EDTA) or a salt thereof, and optionallyone or more of: preservative, a pH adjuster, a fragrance and a coloringagent.

In some embodiments, the present invention provides a gel composition,consisting of about 0.05 wt % fluticasone or a pharmaceuticallyacceptable salt thereof, about 20 wt % propylene glycol, about 1.75 wt %of hydroxyethyl cellulose, about 5 wt % Polysorbate 20, water, about0.02 wt % ethylenediaminetetracetic acid (EDTA) or a salt thereof, andoptionally one or more of: preservative, a pH adjuster, a fragrance anda coloring agent.

In some embodiments, the present invention provides a gel compositioncomprising or consisting essentially of:

(i) an active agent selected from a steroid;

(ii) a first solvent selected from a glycol solvent;

(iii) a second solvent selected from an alkyl alcohol solvent;

(iv) a non-carbomer rheology modifier selected from a hydroxylcellulose;

(v) a solubolzing agent selected from a polysorbate solubilizing agent;and optionally one or more of: an additional solubilizing agent, adiluent, a preservative, a pH adjuster, a chelating agent, a coloringagent, and a fragrance.

In some embodiments, the present invention provides a gel compositionwherein the active agent a steroid or a salt thereof. In someembodiments, the present invention provides a gel composition whereinthe active agent is fluticasone propionate.

In some embodiments, the present invention provides a gel pharmaceuticalcomposition, comprising or consisting essentially of fluticasone orpharmaceutically acceptable salt thereof, in an amount of from about0.01 wt % to about 0.1 wt %, propylene glycol in an amount of about 20wt %, ethanol in an amount of about 19 wt %, hydroxyethyl cellulose inan amount of about 1.75 wt %, Polysorbate 20 in an amount of about 5 wt%, water, and optionally one or more of: a pH adjuster, a chelatingagent, a preservative, a fragrance, and a coloring agent. In certainembodiments, the gel composition is as described above, with theexception that Polysorbate 20 is replaced with Polysorbate 80.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of fluticasone or pharmaceuticallyacceptable salt thereof, in an amount of from about 0.01 wt % to about0.075 wt %, about 20 wt % propylene glycol, about 19 wt % ethanol, about1.75 wt % hydroxyethyl cellulose, about 5 wt % Polysorbate 20, water,ethylenediaminetetracetic acid (EDTA) or a salt thereof, benzyl alcohol,and optionally one or more of: a pH adjuster, a fragrance and a coloringagent. In certain embodiments, the gel composition is as describedabove, with the exception that Polysorbate 20 is replaced withPolysorbate 80.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of fluticasone or pharmaceuticallyacceptable salt thereof, in an amount of from about 0.01 wt % to about0.075 wt %, about 20 wt % propylene glycol, about 19 wt % ethanol, about1.75 wt % hydroxyethyl cellulose, about 5 wt % Polysorbate 20, water,about 0.02 wt % ethylenediaminetetracetic acid (EDTA) or a salt thereof,about 1.0 wt % benzyl alcohol, and optionally one or more of: a pHadjuster, a fragrance and a coloring agent. In certain embodiments, thegel composition is as described above, with the exception thatPolysorbate 20 is replaced with Polysorbate 80.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of fluticasone or pharmaceuticallyacceptable salt thereof in an amount of about 0.01 wt %, 0.015 wt %,0.02 wt %, 0.025 wt %, 0.03 wt %, 0.035 wt %, 0.04 wt %, 0.045 wt %,0.05 wt %, 0.055 wt %, 0.06 wt %, 0.065 wt %, 0.07 wt %, or 0.075 wt %,about 20 wt % propylene glycol, about 19 wt % ethanol, about 1.75 wt %hydroxyethyl cellulose, about 5 wt % Polysorbate 20, water, about 0.02wt % ethylenediaminetetracetic acid (EDTA) or a salt thereof, about 1.0wt % benzyl alcohol, and optionally one or more of: a pH adjuster, afragrance and a coloring agent. In certain embodiments, the gelcomposition is as described above, with the exception that Polysorbate20 is replaced with Polysorbate 80.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of fluticasone or pharmaceuticallyacceptable salt thereof in an amount of about 0.025 wt % or about 0.05wt %, propylene glycol in an amount of about 20 wt %, ethanol in anamount of about 19 wt %, Polysorbate 20 in an amount of about 5 wt %,hydroxyethyl cellulose in an amount of about 1.75 wt %, and water. Incertain embodiments, the gel composition is as described above, with theexception that Polysorbate 20 is replaced with Polysorbate 80.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of fluticasone or pharmaceuticallyacceptable salt thereof in an amount of about 0.025 wt % or about 0.05wt %, about 20 wt % propylene glycol, about 19 wt % ethanol, about 1.75wt % hydroxyethyl cellulose, about 5 wt % Polysorbate 20, water, about0.02 wt % ethylenediaminetetracetic acid (EDTA) or a salt thereof, about1.0 wt % benzyl alcohol, and optionally one or more of: a pH adjuster, afragrance and a coloring agent. In certain embodiments, the gelcomposition is as described above, with the exception that Polysorbate20 is replaced with Polysorbate 80.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of fluticasone propionate in anamount of about 0.025 wt % or about 0.05 wt %, about 20 wt % propyleneglycol, about 19 wt % ethanol, about 1.75 wt % hydroxyethyl cellulose,about 5 wt % Polysorbate 20, water, about 0.02 wt %ethylenediaminetetracetic acid (EDTA) or a salt thereof, about 1.0 wt %benzyl alcohol, and optionally one or more of: a pH adjuster, afragrance and a coloring agent. In certain embodiments, the gelcomposition is as described above, with the exception that Polysorbate20 is replaced with Polysorbate 80.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of fluticasone propionate in anamount of about 0.025 wt % or about 0.05 wt %, about 20 wt % propyleneglycol, about 19 wt % ethanol, about 1.75 wt % hydroxyethyl cellulose,about 5 wt % Polysorbate 20, water, about 0.17 wt % trolamine, about0.02 wt % ethylenediaminetetracetic acid (EDTA) or a salt thereof, andabout 1.0 wt % benzyl alcohol. In certain embodiments, the gelcomposition is as described above, with the exception that Polysorbate20 is replaced with Polysorbate 80.

In some embodiments, the present invention provides a gel compositionfor topical administration consisting essentially of:

(i) fluticasone or a pharmaceutically acceptable salt thereof, presentin an amount of from about 0.01 wt % to about 0.075 wt %;

(ii) a first solvent which is a glycol solvent present in an amount offrom about 10 wt % to about 25 wt %;

(iii) a second solvent which is an alcohol solvent present in an amountof from about 10 wt % to about 25 wt %;

(iv) a non-carbomer rheology modifier; and optionally one or more of: asolubilizing agent, water, a preservative, a pH adjuster, a chelatingagent, a coloring agent, and a fragrance.

In certain embodiments, the gel composition is as described above,wherein the fluticasone or a pharmaceutically acceptable salt thereof ispresent in an amount of about 0.025 wt % or 0.05 wt %. In certainembodiments, the gel composition is as described above, wherein theglycol solvent is present in an amount of about 18 wt % to about 22 wt%. In certain embodiments, the gel composition is as described above,wherein the glycol solvent is propylene glycol. In certain embodiments,the gel composition is as described above, wherein the alcohol ispresent in an amount of from about 17 wt % to about 22 wt %. In certainembodiments, the gel composition is as described above, wherein thealcohol is ethanol. In certain embodiments, the gel composition is asdescribed above, wherein the non-carbomer rheology modifier is a hydroxycellulose. In certain embodiments, the gel composition is as describedabove, wherein the hydroxy cellulose is present in an amount of fromabout 0.75 wt % to about 2.25 wt %. In certain embodiments, the gelcomposition is as described above, wherein the hydroxy cellulosehydroxyethyl cellulose. In certain embodiments, the gel composition isas described above, wherein at least one of the one or more solubilizingagents is a polysorbate solubilizing agent. In certain embodiments, thegel composition is as described above, wherein the polysorbatesolubilizing agent is present in an amount of from about 3 wt % to about8 wt %. In certain embodiments, the gel composition is as describedabove, wherein the polysorbate solubilizing agent is Polysorbate 20 orPolysorbate 80. In certain embodiments, the gel composition is asdescribed above, wherein the fluticasone or pharmaceutically acceptablesalt thereof is fluticasone propionate. In certain embodiments, the gelcomposition is as described above, wherein the fluticasone or apharmaceutically acceptable salt thereof (e.g., fluticasone propionate)is present in an amount of about 0.025 wt % or about 0.05 wt %, theglycol solvent (e.g., propylene glycol) is present in an amount of about20 wt %, the alcohol solvent (e.g., ethanol) is present in an amount ofabout 19 wt %, the non-carbomer rheology modifier (e.g., hydroxyethylcellulose) is present in an amount of about 1.75 wt %, and thesolubilizing agent is a polysorbate (e.g., Polysorbate 20 or Polysorbate80) present in an amount of about 5 wt %.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of from about 0.01 wt % to about1.0 wt % fluticasone, or a pharmaceutically acceptable salt thereof,from about 10 wt % to about 30 wt % of a first solvent, from about 0.75wt % to about 2.25 wt % of a non-carbomer rheology modifier, from about1 wt % to less than about 10 wt % of a first solubilizing agent, fromabout 1 wt % to less than about 10 wt % of a second solubilizing agent,optionally a third solubilizing agent, and optionally one or more of: adiluent, a pH adjuster, a chelating agent, a preservative, a fragrance,and a coloring agent.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of from about 0.01 wt % to about1.0 wt % fluticasone, or a pharmaceutically acceptable salt thereof,from about 15 wt % to about 25 wt % of a first solvent, from about 0.75wt % to about 2.25 wt % of a non-carbomer rheology modifier, from about1 wt % to less than about 10 wt % of a first solubilizing agent, fromabout 1 wt % to less than about 10 wt % of a second solubilizing agent,optionally a third solubilizing agent, and optionally one or more of: adiluent, a pH adjuster, a chelating agent, a preservative, a fragrance,and a coloring agent.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of from about 0.01 wt % to about0.5 wt % fluticasone, or a pharmaceutically acceptable salt thereof,from about 15 wt % to about 25 wt % of a first solvent, from about 0.75wt % to about 2.25 wt % of a non-carbomer rheology modifier, from about1 wt % to less than about 10 wt % of a first solubilizing agent,fromabout 1 wt % to less than about 10 wt % of a second solubilizing agent,optionally a third solubilizing agent, and optionally one or more of: adiluent, a pH adjuster, a chelating agent, a preservative, a fragrance,and a coloring agent.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of from about 0.01 wt % to about0.5 wt % fluticasone, or a pharmaceutically acceptable salt thereof,from about 15 wt % to about 25 wt % of a glycol solvent, from about 0.75wt % to about 2.25 wt % of a hydroxyl cellulose, from about 1 wt % toless than about 10 wt % of a polysorbate solubilizing agent, from about1 wt % to less than about 10 wt % of a second solubilizing agent,optionally a third solubilizing agent, and optionally one or more of: adiluent, a pH adjuster, a chelating agent, a preservative, a fragrance,and a coloring agent.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of from about 0.01 wt % to about0.1 wt % fluticasone, or a pharmaceutically acceptable salt thereof,from about 15 wt % to about 25 wt % of a glycol solvent, from about 0.75wt % to about 2.25 wt % of a hydroxy cellulose, from about 3 wt % toabout 8 wt % of a polysorbate solubilizing agent, from about 1 wt % toless than about 10 wt % of a second solubilizing agent, optionally athird solubilizing agent, and optionally one or more of: a diluent, a pHadjuster, a chelating agent, a preservative, a fragrance, and a coloringagent.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of from about 0.01 wt % to about0.1 wt % fluticasone, or a pharmaceutically acceptable salt thereof,from about 15 wt % to about 25 wt % propylene glycol, from about 0.75 wt% to about 2.25 wt % hydroxyethyl cellulose, from about 3 wt % to about8 wt % Polysorbate 20, from about 1 wt % to less than about 10 wt % of asecond solubilizing agent,optionally a third solubilizing agent, andoptionally one or more of: a diluent, a pH adjuster, a chelating agent,a preservative, a fragrance, and a coloring agent.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of from about 0.01 wt % to about0.1 wt % fluticasone, or a pharmaceutically acceptable salt thereof,from about 15 wt % to about 25 wt % propylene glycol, from about 1.5 wt% to about 2.0 wt % hydroxyethyl cellulose, from about 3 wt % to about 8wt % Polysorbate 20, from about 1 wt % to less than about 10 wt % of asecond solubilizing agent selected from an alcohol or glycol ethersolubilizing agent, optionally from about 1 wt % to less than about 10wt % of a third solubilizing agent, and optionally one or more of: adiluent, a pH adjuster, a chelating agent, a preservative, a fragrance,and a coloring agent.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of from about 0.01 wt % to about0.075 wt % fluticasone, or a pharmaceutically acceptable salt thereof,from about 15 wt % to about 25 wt % propylene glycol, from about 1.5 wt% to about 2.0 wt % hydroxyethyl cellulose, from about 3 wt % to about 8wt % Polysorbate 20, from about 1 wt % to less than about 10 wt % of asecond solubilizing agent selected from an alcohol or glycol ethersolubilizing agent, optionally from about 1 wt % to less than about 10wt % of a third solubilizing agent selected from an alcohol or glycolether solubilizing agent, and optionally one or more of: a diluent, a pHadjuster, a chelating agent, a preservative, a fragrance, and a coloringagent.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of about 0.025 wt % fluticasone, ora pharmaceutically acceptable salt thereof, about 20 wt % propyleneglycol, about 1.75 wt % hydroxyethyl cellulose, about 5 wt % Polysorbate20, about 5 wt % ethanol, and optionally one or more of: a diluent, a pHadjuster, a chelating agent, a preservative, a fragrance, and a coloringagent. In certain embodiments, the gel composition is as described aboveand further comprises diethylene glycol monoethylether in an amount offrom about 1 wt % to about 3 wt %. For instance, in certain embodiments,the present invention provides a gel composition, comprising orconsisting essentially of about 0.025 wt % fluticasone, or apharmaceutically acceptable salt thereof, about 20 wt % propyleneglycol, about 1.75 wt % hydroxyethyl cellulose, about 5 wt % Polysorbate20, about 5 wt % ethanol, about 1.5 wt % diethylene glycolmonoethylether, and optionally one or more of: a diluent, a pH adjuster,a chelating agent, a preservative, a fragrance, and a coloring agent.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of about 0.05 wt % fluticasone, ora pharmaceutically acceptable salt thereof, about 20 wt % propyleneglycol, about 1.75 wt % hydroxyethyl cellulose, about 5 wt % Polysorbate20, about 5 wt % ethanol, and optionally one or more of: a diluent, a pHadjuster, a chelating agent, a preservative, a fragrance, and a coloringagent. In certain embodiments, the gel composition is as described aboveand further comprises diethylene glycol monoethylether in an amount offrom about 1 wt % to about 3 wt %. For instance, in certain embodiments,the present invention provides a gel composition, comprising orconsisting essentially of about 0.05 wt % fluticasone, or apharmaceutically acceptable salt thereof, about 20 wt % propyleneglycol, about 1.75 wt % hydroxyethyl cellulose, about 5 wt % Polysorbate20, about 5 wt % ethanol, about 1.5 wt % diethylene glycolmonoethylether, and optionally one or more of: a diluent, a pH adjuster,a chelating agent, a preservative, a fragrance, and a coloring agent.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of about 0.025 wt % fluticasone, ora pharmaceutically acceptable salt thereof, about 20 wt % propyleneglycol, about 1.75 wt % hydroxyethyl cellulose, about 5 wt % Polysorbate20, about 5 wt % ethanol, about 1.5 wt % diethylene glycolmonoethylether, water, 0.02 wt % ethylenediaminetetracetic acid (EDTA)or a salt thereof, and optionally a preservative, a pH adjuster, afragrance, and a coloring agent.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of about 0.05 wt % fluticasone, ora pharmaceutically acceptable salt thereof, about 20 wt % propyleneglycol, about 1.75 wt % hydroxyethyl cellulose, about 5 wt % Polysorbate20, about 5 wt % ethanol, about 1.5 wt % diethylene glycolmonoethylether, water, 0.02 wt % ethylenediaminetetracetic acid (EDTA)or a salt thereof, and optionally a preservative, a pH adjuster, afragrance, and a coloring agent.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of about 0.025 wt % fluticasone, ora pharmaceutically acceptable salt thereof, about 20 wt % propyleneglycol, about 1.75 wt % of hydroxyethyl cellulose, about 5 wt %Polysorbate 20, from about 7 wt % to about 9 wt % ethanol, andoptionally one or more of: a diluent, a pH adjuster, a chelating agent,a preservative, a fragrance, and a coloring agent. For instance, incertain embodiments, the present invention provides a gel composition,comprising or consisting essentially of about 0.025 wt % fluticasone, ora pharmaceutically acceptable salt thereof, about 20 wt % propyleneglycol, about 1.75 wt % of hydroxyethyl cellulose, about 5 wt %Polysorbate 20, about 8 wt % ethanol, water, 0.02 wt %ethylenediaminetetracetic acid (EDTA) or a salt thereof, and optionallya preservative, a pH adjuster, a fragrance, and a coloring agent. Incertain embodiments, the gel composition is as described above andfurther comprises diethylene glycol monoethylether in an amount of fromabout 1 wt % to about 3 wt %.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of about 0.05 wt % fluticasone, ora pharmaceutically acceptable salt thereof, about 20 wt % propyleneglycol, about 1.75 wt % of hydroxyethyl cellulose, about 5 wt %Polysorbate 20, from about 7 wt % to about 9 wt % ethanol, andoptionally one or more of: a diluent, a pH adjuster, a chelating agent,a preservative, a fragrance, and a coloring agent. For instance, incertain embodiments, the present invention provides a gel composition,comprising or consisting essentially of about 0.05 wt % fluticasone, ora pharmaceutically acceptable salt thereof, about 20 wt % propyleneglycol, about 1.75 wt % of hydroxyethyl cellulose, about 5 wt %Polysorbate 20, about 8 wt % ethanol, water, 0.02 wt %ethylenediaminetetracetic acid (EDTA) or a salt thereof, and optionallya preservative, a pH adjuster, a fragrance, and a coloring agent. Incertain embodiments, the gel composition is as described above andfurther comprises diethylene glycol monoethylether in an amount of fromabout 1 wt % to about 3 wt %.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of about 0.025 wt % fluticasone, ora pharmaceutically acceptable salt thereof, about 20 wt % propyleneglycol, about 1.5 wt % to about 2.0 wt % hydroxyethyl cellulose, fromabout 3 wt % to about 8 wt % Polysorbate 20, from about 1 wt % to about3 wt % of a glycol ether solubilizing agent, and optionally one or moreof: a diluent, a pH adjuster, a chelating agent, a preservative, afragrance, and a coloring agent. For instance, in certain embodiments,the present invention provides a gel composition, comprising orconsisting essentially of about 0.025 wt % fluticasone, or apharmaceutically acceptable salt thereof, about 20 wt % propyleneglycol, about 1.75 wt % hydroxyethyl cellulose, about 5 wt % Polysorbate20, about 1.5 wt % diethylene glycol monoethylether, water, 0.02 wt %ethylenediaminetetracetic acid (EDTA) or a salt thereof, and optionallya preservative, a pH adjuster, a fragrance, and a coloring agent.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of about 0.05 wt % fluticasone, ora pharmaceutically acceptable salt thereof, about 20 wt % propyleneglycol, about 1.5 wt % to about 2.0 wt % hydroxyethyl cellulose, fromabout 3 wt % to about 8 wt % Polysorbate 20, from about 1 wt % to about3 wt % of a glycol ether solubilizing agent, and optionally one or moreof: a diluent, a pH adjuster, a chelating agent, a preservative, afragrance, and a coloring agent. For instance, in certain embodiments,the present invention provides a gel composition, comprising orconsisting essentially of about 0.05 wt % fluticasone, or apharmaceutically acceptable salt thereof, about 20 wt % propyleneglycol, about 1.75 wt % hydroxyethyl cellulose, about 5 wt % Polysorbate20, about 1.5 wt % diethylene glycol monoethylether, water, 0.02 wt %ethylenediaminetetracetic acid (EDTA) or a salt thereof, and optionallya preservative, a pH adjuster, a fragrance, and a coloring agent.

In some embodiments, gel compositions described above and hereincomprise about 0.1 wt % fluticasone, or a pharmaceutically acceptablesalt or ester thereof. For instance, in some embodiments, gelcompositions described above and herein comprise about 0.1 wt %fluticasone propionate.

In some embodiments, the present invention provides a gel composition,comprising or consisting essentially of about 0.1 wt % fluticasone, or apharmaceutically acceptable salt or ester thereof, about 20 wt %propylene glycol, about 1.75 wt % hydroxyethyl cellulose, about 5 wt %Polysorbate 20, about 1.5 wt % diethylene glycol monoethylether, water,0.02 wt % ethylenediaminetetracetic acid (EDTA) or a salt thereof, 1.0wt % benzyl alcohol, and optionally a preservative, a pH adjuster, afragrance, and a coloring agent.

Methods of Treatment

The presently described subject matter relates to a method of treating acondition, disease or disorder in a subject, comprising: topicallyadministering to a subject in need thereof, a therapeutically effectiveamount of any presently described topical gel composition. In someembodiments, the present invention provides a method for treating asuperficial disease, disorder, or condition in a subject, comprisestopically administering to the subject a therapeutically effectiveamount of a provided topical gel composition. In some embodiments, thesuperficial disease, disorder, or condition is selected from asuperficial microbial infection or an inflammatory disease, disorder, orcondition.

Methods of Treating Microbial Infections

In some embodiments, the present invention provides a method of treatinga microbial infection in a subject, comprising: topically administeringto a subject in need thereof a therapeutically effective amount of anypresently described topical gel composition useful in treating amicrobial infection.

In some embodiments, administration of a provided gel compositionreduces the number of microbes, preferably pathogenic microbes, in or onthe mammal to which it is administered. The microbes that can be actedon by the present compositions are selected from the group consisting offungi, molds, yeast and combinations thereof.

In some embodiments, the presently described subject matter relates to amethod for treating a condition, disease or disorder in a subject,wherein the condition, disease or disorder is a fungal infection. Incertain embodiments, the fungal infection is a fungal infection of theskin. In certain embodiments, the fungal infection is a fungal infectionof the nail. In certain embodiments, the fungal infection is a fungalinfection of the hair follicle.

In some embodiments, the presently described subject matter relates tothe use of a presently described composition to treat a microbialinfection in a subject by topically administering the composition to thesubject in need thereof.

In some embodiments, the presently described subject matter relates tothe use of a presently described composition to treat a fungal infectionin a subject by topically administering the composition to the subjectin need thereof.

In some embodiments, the presently described subject matter relates tothe use of an antifungal agent or a pharmaceutically salt thereof in themanufacture of a medicament for the treatment of a fungal infection.

In some embodiments, the presently described subject matter relates tothe use of naftifine, or a pharmaceutically salt thereof, in themanufacture of a medicament for the treatment of a fungal infection.

In some embodiments, conditions treated by administration of a providedcomposition include superficial fungal infections of the skin thatappear on the outer layer of skin and can cause Tinea cruris (jockitch), Tinea corporis (ringworm), Tinea pedis, interdigital Tinea pedis,moccasin-type Tinea pedis, Tinea manuum, Tinea versicolor (piyriasis),Tinea nigra, cutaneous candidiasis, Tinea faciei (facial ringworm), andwhite and black piedra.

Tinea corporis (body ringworm), Tinea cruris (jock itch), and Tineafaciei (facial ringworm), may be caused by Epidermophyton floccosum,Microsporum canis, Trichophyton mentagrophytes, T. rubrum, T. tonsurans,T. verrucosum, and/or T. violaceum, and are treatable by theadministration of the present compositions.

Tinea pedis (athlete's foot) or Tinea manuum (fungal infection of thehand), which may be caused Epidermophyton floccosum, Microsporum canis,Trichophyton mentagrophytes, T. rubrum, T. tonsurans, T. verrucosum,and/or T. violaceum, are treatable by the administration of the presentcompositions.

Cutaneous candidiasis, which may be caused by Candida albicans, may alsobe treatable by the administration of the present compositions.

Antifungal agents, for example, naftifine, or a pharmaceuticallyacceptable salt thereof have fungicidal activity against multipleorganisms. Accordingly, the administration of the present compositionsmay treat, for example, superficial fungal infections of the skinrelated to or caused by Epidermophyton floccosum, Microsporum canis,Microsporum gypseum, Trichophyton mentagrophytes, T. interdigitale, T.rubrum, T. soudanense, T. tonsurans, T. verrucosum, T. violaceum, andCandida albicans.

In some embodiments, the present subject matter also relates to a methodof treating and/or preventing a fungal infection of the hair follicle,including for example, one or more of Tinea capitis, Tinea favosa, andTinea barbae, in a mammal comprising administering to a mammal in needthereof an effective amount of presently described gel composition.

In some embodiments, conditions treated by administration of a providedcomposition include Tinea capitis and/or Tinea favosa and/or Tineabarbae.

Tinea capitis and/or Tinea favosa and/or Tinea barbae are treatable bythe administration of a provided composition.

Tinea capitis is a superficial fungal infection (dermatophytosis) of theskin of the scalp, eyebrows, and eyelashes, that attacks the hair shaftand follicles. The disease is primarily caused by dermatophytes in theTrichophyton and Microsporum genera, including for example, Microsporumaudouini, Microsporum canis, Microsporum Microsporum distortum,Microsporum gypseum, Trichophyton megninii, Trichophyton mentagrophytes,Trichophyton rubrum, Trichophyton schoenleinii, Trichophyton tonsurans,and Trichophyton verrucosum. The clinical presentation is typically asingle or multiple patches of hair loss, sometimes with a ‘black dot’pattern (often with broken-off hairs), that may be accompanied byinflammation, scaling, pustules, and itching. Tinea favosa can beconsidered a variety of Tinea capitis because it involves the scalp.Tinea favosa is primarily caused by dermatophytes in the Trichophytonand Microsporum genera, including for example, Microsporum gypseum andTrichophyton schoenleinii. Tinea barbae is a superficial dermatophytosisthat is limited to the bearded areas of the face and neck and occursalmost exclusively in older adolescent and adult males. The clinicalpresentation of Tinea barbae includes inflammatory, deep, kerion-likeplaques and non-inflammatory superficial patches resembling Tineacorporis or bacterial folliculitis. The mechanism that causes Tineabarbae is similar to that of Tinea capitis, and is frequently the resultof a Trichophyton rubrum (T. rubrum) infection but may also be theresult of Trichophyton mentagrophytes var granulosum and Trichophytonverrucosum. Finally Microsporum canis and Trichophyton mentagrophytesvar erinacei have been known to cause Tinea barbae but are relativelyrare.

Tinea capitis which may be caused by one or more of Microsporumaudouini, Microsporum canis, Microsporum Microsporum distortum,Microsporum gypseum, Trichophyton megninii, Trichophyton mentagrophytes,Trichophyton rubrum, Trichophyton schoenleinii, Trichophyton tonsurans,and/or Trichophyton verrucosum, and Tinea favosa which may be caused byone or more of Microsporum gypseum and/or Trichophyton schoenleinii, andTinea barbae which may be caused by one of more of Trichophyton rubrum(T. rubrum), Trichophyton mentagrophytes var granulosum, Trichophytonverrucosum, Microsporum canis and Trichophyton mentagrophytes varerinacei, are treatable by the administration of the presentcompositions.

Antifungal agents, for example, naftifine, or a pharmaceuticallyacceptable salt thereof have fungicidal activity against multipleorganisms. Accordingly, the administration of the present compositionsmay treat, for example, conditions related to or caused by Microsporumaudouini, Microsporum canis, Microsporum distortum, Microsporum gypseum,Trichophyton megninii, Trichophyton mentagrophytes var granulosum,Trichophyton mentagrophytes var erinacei, Trichophyton rubrum,Trichophyton schoenleinii, Trichophyton tonsurans, and/or Trichophytonverrucosum.

In some embodiments, the present subject matter relates to a method oftreating and/or preventing onychomycosis in a subject comprisingadministering to a subject in need thereof an effective amount ofpresently described gel composition.

Non-limiting conditions that are treated by the administration of thepresent compositions include onychomycosis including onychomycosiscaused by one or more of dermatophytes, yeasts (candidal onychomycosis),and non-dermatophyte molds.

Onychomycosis is treatable by the administration of the presentcompositions.

Onychomycosis is a fungal infection of the nail bed, matrix, and/or ornail plate. It is caused by 3 main classes of fungi: dermatophytes,yeasts (candidal onychomycosis), and nondermatophyte molds.Dermatophytes are the most common cause of onychomycosis. onychomycosiscaused by non-dermatophyte molds is becoming more common worldwide.onychomycosis due to Candida is less common. Dermatophytes that cancause onychomycosis include one or more of Trichophyton rubrum,Trichophyton interdigitale, Epidermophyton floccosum, Trichophytonviolaceum, Microsporum gypseum, Trichophyton tonsurans, Trichophytonsoudanense, and Trichophyton verrucosum, and dermatophyte associatedonychomycosis is often also referred to as Tinea ungium. Candidalonychomycosis include cutaneous candidisis and mucocutaneouscandidiasis, that are caused by one or more Candida species, includingfor example, Candida albicans and Candida parapsilosis. Non-dermatophytemolds that can cause onychomycosis can include one or more of, forexample, Scopulariopsis brevicaulis, Fusarium spp., Aspergillus spp.,Alternaria, Acremonium, Scytalidinum dimidiatum, and Scytalidiniumhyalinum.

There are four classic types of onychomycosis including the following:distal subungual onychomycosis (DLSO) that is the most common form ofonychomycosis, and is usually caused by Trichophyton rubrum and/orTrichophyton interdigitale, which invades the nail bed and the undersideof the nail plate; white superficial onychomycosis (WSO) is caused byfungal (e.g., T. mentagrophytes) invasion of the superficial layers ofthe nail plate to form “white islands” on the plate, nondermatophytemolds cause deep white superficial onychomycosis; proximal subungualonychomycosis (PSO) is fungal penetration of the newly formed nail platethrough the proximal nail fold and it is the least common form ofonychomycosis in healthy people, but is found more commonly when thepatient is immunocompromised; endonyx onychomycosis (EO), and candidalonychomycosis (CO) which is Candida species invasion of the fingernails.

Antifungal agents, for example, naftifine, or a pharmaceuticallyacceptable salt thereof have fungicidal activity against multipleorganisms. Accordingly, the administration of the present compositionsmay treat, for example, conditions, including for example,onychomycosis, related to or caused by one or more dermatophytes,including for example, Trichophyton rubrum, Trichophyton interdigitale,Epidermophyton floccosum, Trichophyton violaceum, Microsporum gypseum,Trichophyton tonsurans, Trichophyton soudanense, and Trichophytonverrucosum; caused by one or more Candida species, including forexample, Candida albicans and Candida parapsilosis; and/or caused by oneor more molds, including for example, Scopulariopsis brevicaulis, aFusarium spp., a Aspergillus spp., Alternaria, Acremonium, Scytalidinumdimidiatum, and Scytalidinium hyalinum.

In some embodiments, the present invention provides a gel composition asdescribed above and herein, wherein the composition is combined with aphysical/mechanical penetration enhancer that, for example, acts byincreasing permeability by reversibly damaging or altering thephysicochemical nature of the stratum corneum or nail surface to reduceits diffusional resistance. Such mechanical enhancement can includethose known in the art such as manual and electrical nail abrasion, acidetching, ablation by laser, microporation, iontophoresis, application oflow-frequency ultrasound, heat or electric currents on/through the nailor skin to make the diffusion of topical moieties more efficient.

Methods of Treating Inflammatory Diseases, Disorders, and Conditions

In some embodiments, the presently described subject matter relates to amethod of treating a superficial inflammatory disease, disorder, orcondition in a subject, comprising: topically administering to a subjectin need thereof a therapeutically effective amount of any presentlydescribed topical gel composition useful in treating aninflammatorydisease, disorder, or condition of the skin.

Exemplary such inflammatory diseases, disorders, and conditions of theskin include, but are not limited to, atopic dermatitis, psoriasis,eczema, acne, rosacea, and lichenoid disorders.

In some embodiments, treatment of an inflammatory disease (e.g. atopicdermatitis), disorder, or condition of the skin comprises topicaladministration of a provided gel composition comprising a steroid.Exemplary such steroids are described above. In some embodiments, thesteroid is a corticosteroid. In some embodiments, the steroid isfluticasone, or a pharmaceutically acceptable salt thereof. In certainembodiments, the steroid is fluticasone propionate.

In some embodiments, the presently described subject matter relates tothe use of a presently described composition to treat a superficialinflammatory disease, disorder, or condition in a subject by topicallyadministering the composition to the subject in need thereof

In some embodiments, the presently described subject matter relates tothe use of a presently described composition to treat atopic dermatitisin a subject by topically administering the composition to the subjectin need thereof.

In some embodiments, the presently described subject matter relates tothe use of a steroid or a pharmaceutically salt thereof in themanufacture of a medicament for the treatment of a superficialinflammatory disease, disorder, or condition.

In some embodiments, the presently described subject matter relates tothe use of fluticasone, or a pharmaceutically salt thereof, in themanufacture of a medicament for the treatment of atopic dermatitis.

Administration

The presently described gel compositions can be topically administeredin any formulation, including a gel. A sufficient amount of the topicalpreparation can be gently rubbed onto the affected area and surroundingskin, for example, in an amount sufficient to cover an affected areaplus a margin of healthy skin or tissue surrounding the affected area,for example, a margin of about 0.5 inches. The compositions can beapplied to any body surface, including for example, a skin surface,scalp, eyebrows, eyelashes, bearded areas, nail surface, nail bed, nailmatrix, and nail fold, as well as to the mouth, vagina, eye, nose, orother mucous membranes.

For most superficial fungal infections of the skin, the composition canbe applied in a single, one-time application, once a week, once abi-week, once a month, or from one to four times daily, for a period oftime sufficient to alleviate symptoms or clear the fungal infection, forexample, for a period of time of one week, from 1 to 12 weeks or more,from 1 to 10 weeks, from 1 to 8 weeks, from 2 to 12 weeks, from 2 to 10weeks, from 2 to 8 weeks, from 2 to 6 weeks, from 2 to 4 weeks, from 4to 12 weeks, from 4 to 10 weeks, from 4 to 8 weeks, from 4 to 6 weeks.The present compositions can be administered, for example, at afrequency of once per day or twice per day. The presently describedcompositions can be topically administered once per day for a period oftime from 1 week to 8 weeks, from 1 week to 4 weeks, for 1 week, for 2weeks, for 3 weeks, for 4 weeks, for 5 weeks, for 6 weeks, for 7 weeks,or for 8 weeks.

The presently described compositions can be applied in a therapeuticallyeffective amount, for example, an amount sufficient to cover an affectedarea plus a margin of healthy skin or tissue surrounding the affectedarea, for example, a margin of about 0.5 inches. Suitable amounts, forexample, per application per affected area or cumulative daily dosageper affected area (for example two applications in a 24 hour period),can include, for example, from about 0.1 grams to about 8 grams; fromabout 0.2 grams to about 4.5 grams; from about 0.3 grams to about 4grams; from about 0.4 grams to about 3.5 grams; from about 0.4 grams toabout 3 grams; from about 0.4 grams to about 2.5 grams; from about 0.4grams to about 2 grams; from about 0.4 grams to about 1.5 grams; fromabout 0.5 grams to about 8 grams; from about 0.5 grams to about 6 grams;from about 0.5 grams to about 5 grams; from about 0.5 grams to about 4.5grams; from about 0.5 grams to about 4 grams; from about 0.5 grams toabout 3.5 grams; from about 0.5 grams to about 3 grams; from about 0.5grams to about 2.5 grams; from about 0.5 grams to about 2 grams; fromabout 0.5 grams to about 1.5 grams; from about 0.5 grams to about 1gram; from about 1 gram to about 8 grams; from about 1 gram to about 8grams; from about 1 gram to about 7 grams; from about 1 gram to about 6grams; from about 1 gram to about 5 grams; from about 1 gram to about4.5 grams; from about 1 gram to about 4 grams; from about 1 gram toabout 3.5 grams; from about 1 gram to about 3 grams; from about 1 gramto about 2.5 grams; from about 1 gram to about 2 grams; from about 1gram to about 1.5 grams; from about 1.5 grams to about 8 grams; fromabout 1.5 grams to about 7 grams; from about 1.5 grams to about 6 grams;from about 1.5 grams to about 5 grams; from about 1.5 grams to about 4.5grams; from about 1.5 grams to about 4 grams; from about 1.5 grams toabout 3.5 grams; from about 1.5 grams to about 3 grams; from about 1.5grams to about 2.5 grams; from about 1.5 grams to about 2 grams; fromabout 2 grams to about 8 grams; from about 2 grams to about 7 grams;from about 2 grams to about 6 grams; from about 2 grams to about 5grams; from about 2 grams to about 4.5 grams; from about 2 grams toabout 4 grams; from about 2 grams to about 3.5 grams; from about 2 gramsto about 3 grams; from about 2 grams to about 2.5 grams; from about 2.5grams to about 8 grams; from about 2.5 grams to about 7 grams; fromabout 2.5 grams to about 6 grams; from about 2.5 grams to about 5 grams;from about 2.5 grams to about 4.5 grams; from about 2.5 grams to about 4grams; from about 2.5 grams to about 3.5 grams; from about 2.5 grams toabout 3 grams; from about 3 grams to about 8 grams; from about 3 gramsto about 7 grams; from about 3 grams to about 6 grams; from about 3grams to about 5 grams; from about 3 grams to about 4.5 grams; fromabout 3 grams to about 4 grams; from about 3 grams to about 3.5 grams;from about 3.5 grams to about 8 grams; from about 3.5 grams to about 7grams; from about 3.5 grams to about 6 grams; from about 3.5 grams toabout 5 grams; from about 3.5 grams to about 4.5 grams; from about 3.5grams to about 4 grams; from about 4 grams to about 8 grams; from about4 grams to about 7 grams; from about 4 grams to about 6 grams; fromabout 4 grams to about 5 grams; from about 4 grams to about 4.5 grams;from about 4.5 grams to about 8 grams; from about 4.5 grams to about 7grams; from about 4.5 grams to about 6 grams; from about 4.5 grams toabout 5 grams; from about 5 grams to about 8 grams; from about 5 gramsto about 7 grams; from about 5 grams to about 6 grams; from about 5.5grams to about 8 grams; from about 5.5 grams to about 7 grams; fromabout 5.5 grams to about 6 grams; from about 6 grams to about 8 grams;from about 6 grams to about 7 grams; from about 6.5 grams to about 8grams; from about 6.5 grams to about 7 grams; from about 7 grams toabout 8 grams; from about 7.5 grams to about 8 grams; about 0.2 grams;about 0.5 grams; about 1 gram; about 1.5 grams; about 2 grams; about 2.5grams; about 3 grams, about 3.5 grams; about 4 grams, about 4.5 grams;about 5 grams, about 5.5 grams; about 6 grams, about 6.5 grams; about 7grams, about 7.5 grams; or about 8 grams.

In certain severe cases, for example, of Tinea pedis and/or Tineacruris, a maximum per application, per affected area, dose of 8 grams ofthe presently described composition can be applied to an affected area,for example, once or twice daily.

For example, generally for Tinea corporis or Tinea cruris or Tineafaciei, the present composition can be applied, for example once ortwice daily, for example, morning and evening, for about 2-4 weeks.Generally for Tinea pedis application the present composition can beapplied once daily, for 2 weeks or longer. For example, the presentlydescribed compositions can be topically applied in an amount sufficientto cover an affected area plus a margin of healthy skin or tissuesurrounding the affected area, for example, a margin of about 0.5inches, at a frequency, for example, of once a day, for a time period,for example of about two weeks.

If desired, other therapeutic agents can be employed in conjunction withthose provided in the above-described compositions. The amount ofpharmaceutically active ingredients that may be combined with thecarrier materials to produce a single dosage form will vary dependingupon the host treated, the nature of the disease, disorder, orcondition, and the nature of the active ingredients.

In some embodiments, the pharmaceutical compositions are given in asingle or multiple doses per time period, for example, daily, weekly,bi-weekly, or monthly. For example, in some embodiments, thepharmaceutical compositions are given from one to four times per period.

In some embodiments, for superficial fungal infections of the skin, thepresent compositions are given once per week, for a period of from oneto six weeks, for example for one week, for two weeks, for three weeks,for four weeks, five weeks, or for six weeks.

In some embodiments, for onychomycosis infections, the composition areapplied at a frequency of from one to four times daily, including forexample, once daily, twice daily, three times daily, or four timesdaily, one a daily or weekly basis, or on a monthly or every other monthschedule, for a period of time sufficient to alleviate symptoms or clearthe fungal infection, for example, for a period of time of from 1 to 52weeks, from 1 to 26 weeks, from 26 to 52 weeks, from 13 to 39 weeks,from 20 to 40 weeks, from 20 to 48 weeks, from 5 to 50 weeks, from 10 to45 weeks, from 15 to 40 weeks, from 20 to 35 weeks, from 25 to 30 weeks,for about 30 weeks; from 28 weeks to 50 weeks, from 30 week to 48 weeks,from 32 to 46 weeks, from 34 to 44 weeks, from 36 to 42 weeks, from 38to 40 weeks, from 2 to 24 weeks, from 2 to 22 weeks, from 2 to 20 weeks,from 2 to 18 weeks, from 2 to 16 weeks, from 2 to 14 weeks, from 2 to 12weeks, from 2 to 10 weeks, from 2 to 8 weeks, from 2 to 6 weeks, from 2to 4 weeks, from 10 to 48 weeks, from 12 to 48 weeks, from 14 to 48weeks, from 16 to 48 weeks, from 18 to 48 weeks, from 20 to 48 weeks,from 22 weeks to 48 weeks, from 24 week to 48 weeks, from 26 to 48weeks, from 28 to 48 weeks, from 30 to 48 weeks, from 32 to 48 weeks,from 34 to 48 weeks, from 34 to 48 weeks, from 36 to 48 weeks, from 38to 48 weeks, from 40 to 48 weeks, from 42 to 48 weeks, from 44 to 48weeks, from 46 to 48 weeks, for 1 weeks, for 2 weeks, for 4 weeks, for 6weeks, for 8 weeks, for 10 weeks, for 12 weeks, for 24 weeks, for 26weeks, for 28 weeks, for 30 weeks, for 32 weeks, for 34 weeks, for 36weeks, for 38 weeks, for 40 weeks, for 42 weeks, for 44 weeks, for 46weeks, for 48 weeks, for 50 weeks, for 50 weeks, or for 52 weeks. Forexample, the present compositions can be topically administered, at afrequency of once per day for a period of time from 1 week to 52 weeks,for example for about from 24 weeks to 48 weeks.

In some embodiments, for onychomycosis infections the presentlydescribed compositions are applied in a therapeutically effectiveamount, for example, an amount sufficient to cover an affected area plusa margin of healthy skin and/or nail surrounding the affected area, forexample, a margin of about 0.1 to about 0.5 inches. Suitable amounts,for example, per application per affected area or cumulative dailydosage per affected area (one or more nails and, for example, one or twoapplications in a 24 hour period), can include, for example, from about0.1 grams to about 8 grams; from about 0.2 grams to about 4.5 grams;from about 0.3 grams to about 4 grams; from about 0.4 grams to about 3.5grams; from about 0.4 grams to about 3 grams; from about 0.4 grams toabout 2.5 grams; from about 0.4 grams to about 2 grams; from about 0.4grams to about 1.5 grams; from about 0.5 grams to about 8 grams; fromabout 0.5 grams to about 6 grams; from about 0.5 grams to about 5 grams;from about 0.5 grams to about 4.5 grams; from about 0.5 grams to about 4grams; from about 0.5 grams to about 3.5 grams; from about 0.5 grams toabout 3 grams; from about 0.5 grams to about 2.5 grams; from about 0.5grams to about 2 grams; from about 0.5 grams to about 1.5 grams; fromabout 0.5 grams to about 1 gram; from about 1 gram to about 8 grams;from about 1 gram to about 8 grams; from about 1 gram to about 7 grams;from about 1 gram to about 6 grams; from about 1 gram to about 5 grams;from about 1 gram to about 4.5 grams; from about 1 gram to about 4grams; from about 1 gram to about 3.5 grams; from about 1 gram to about3 grams; from about 1 gram to about 2.5 grams; from about 1 gram toabout 2 grams; from about 1 gram to about 1.5 grams; from about 1.5grams to about 8 grams; from about 1.5 grams to about 7 grams; fromabout 1.5 grams to about 6 grams; from about 1.5 grams to about 5 grams;from about 1.5 grams to about 4.5 grams; from about 1.5 grams to about 4grams; from about 1.5 grams to about 3.5 grams; from about 1.5 grams toabout 3 grams; from about 1.5 grams to about 2.5 grams; from about 1.5grams to about 2 grams; from about 2 grams to about 8 grams; from about2 grams to about 7 grams; from about 2 grams to about 6 grams; fromabout 2 grams to about 5 grams; from about 2 grams to about 4.5 grams;from about 2 grams to about 4 grams; from about 2 grams to about 3.5grams; from about 2 grams to about 3 grams; from about 2 grams to about2.5 grams; from about 2.5 grams to about 8 grams; from about 2.5 gramsto about 7 grams; from about 2.5 grams to about 6 grams; from about 2.5grams to about 5 grams; from about 2.5 grams to about 4.5 grams; fromabout 2.5 grams to about 4 grams; from about 2.5 grams to about 3.5grams; from about 2.5 grams to about 3 grams; from about 3 grams toabout 8 grams; from about 3 grams to about 7 grams; from about 3 gramsto about 6 grams; from about 3 grams to about 5 grams; from about 3grams to about 4.5 grams; from about 3 grams to about 4 grams; fromabout 3 grams to about 3.5 grams; from about 3.5 grams to about 8 grams;from about 3.5 grams to about 7 grams; from about 3.5 grams to about 6grams; from about 3.5 grams to about 5 grams; from about 3.5 grams toabout 4.5 grams; from about 3.5 grams to about 4 grams; from about 4grams to about 8 grams; from about 4 grams to about 7 grams; from about4 grams to about 6 grams; from about 4 grams to about 5 grams; fromabout 4 grams to about 4.5 grams; from about 4.5 grams to about 8 grams;from about 4.5 grams to about 7 grams; from about 4.5 grams to about 6grams; from about 4.5 grams to about 5 grams; from about 5 grams toabout 8 grams; from about 5 grams to about 7 grams; from about 5 gramsto about 6 grams; from about 5.5 grams to about 8 grams; from about 5.5grams to about 7 grams; from about 5.5 grams to about 6 grams; fromabout 6 grams to about 8 grams; from about 6 grams to about 7 grams;from about 6.5 grams to about 8 grams; from about 6.5 grams to about 7grams; from about 7 grams to about 8 grams; from about 7.5 grams toabout 8 grams; about 0.2 grams; about 0.5 grams; about 1 gram; about 1.5grams; about 2 grams; about 2.5 grams; about 3 grams, about 3.5 grams;about 4 grams, about 4.5 grams; about 5 grams, about 5.5 grams; about 6grams, about 6.5 grams; about 7 grams, about 7.5 grams; or about 8grams.

In certain onychomycosis cases a maximum per application, per affectedarea, dose of 8 grams of the presently described composition is appliedto an affected area (all nails), for example, once or twice daily. Insome embodiments, the present composition is applied, for example onceor twice daily, for example, morning and/or evening, for about 1-52weeks. For example, in some embodiments, the presently describedcompositions are topically applied in an amount sufficient to cover anaffected area plus a margin of healthy skin and/or nail surrounding theaffected area, for example, a margin of about 0.1 to about 0.5 inches,at a frequency, for example, of once a day, for a time period, forexample of about 24 to about 48 weeks.

EXEMPLIFICATION

The following examples are illustrative of the present pharmaceuticalcompositions and are not intended to be limitations thereon.

Example 1 2% Naftifine Hydrochloride Gel

By way of Example 1, a gel formulation comprising 2% naftifinehydrochloride was prepared according to the present invention. Theformulation is shown in Table 1 below:

TABLE 1 Ingredient % w/w Purified Water USP 51.06 Polysorbate 20 NF 5.00Edetate Disodium USP 0.02 Ethanol 19.00 Propylene Glycol 20.00 NaftifineHydrochloride USP 2.00 Hydroxyethyl Cellulose 1.75 Benzyl Alcohol 1.00Trolamine 0.17 Total 100General Preparation of Naftifine Gel Formulations

In order to formulate the gel, three separate phases, i.e., an alcoholphase, a solubilizing agentphase and a water phase, were prepared andcombined. More specifically, the alcohol phase was prepared by combiningthe propylene glycol, ethanol, and benzyl alcohol, which were mixeduntil uniform. Next, naftifine hydrochloride was added and mixed untildissolved. Hydroxyethyl cellulose was then added and mixed untildispersed.

The solubilizing agent phase was prepared by combining purified water,polysorbate 20 and edetate disodium. The ingredients were mixed untildissolved.

Next, the alcohol phase was combined with the solubilizing agent phaseand mixed together to obtain a mixed phase. To the mixed phase, ethanolwas added, and the resulting product was mixed.

The water phase was prepared by combining trolamine and purified waterand mixing until dissolved. Subsequently, the water phase was combinedwith mixed phases and the product was mixed until hydrated. After that,the product was deaerated with a counter-rotating mixer to obtain a bulkdrug product. The bulk drug product may be transferred to a holding tankand/or packaged.

Example 1a Alternative 2% Naftifine Hydrochloride Gel

An alternative gel formulation comprising 2% naftifine hydrochloride wasprepared according to the present invention. The formulation is shown inTable 1a below:

TABLE 1a Ingredient % w/w Purified Water USP 46.85 Polysorbate 80 NF5.00 Edetate Disodium USP 0.02 Ethanol 44.50 Naftifine Hydrochloride USP2.00 Hydroxypropyl Cellulose 1.50 Diisopropanolamine 0.13 Total 100

Example 2 2.5% Naftifine Hydrochloride Gel

A gel formulation comprising 2.5% naftifine hydrochloride will beprepared in the same manner as the formulation in Example 1. Theformulation is shown in Table 2 below:

TABLE 2 Ingredient % w/w Purified Water USP 50.56 Polysorbate 20 NF 5.00Edetate Disodium USP 0.02 Ethanol 19.00 Propylene Glycol 20.00 NaftifineHydrochloride USP 2.50 Hydroxyethyl Cellulose 1.75 Benzyl Alcohol 1.00Trolamine 0.17 Total 100

Example 3 1.5% Naftifine Hydrochloride Gel

A gel formulation comprising 1.5% naftifine hydrochloride will beprepared in the same manner as the formulation in Example 1. Theformulation is shown in Table 3 below:

TABLE 3 Ingredient % w/w Purified Water USP 51.56 Polysorbate 20 NF 5.00Edetate Disodium USP 0.02 Ethanol 19.00 Propylene Glycol 20.00 NaftifineHydrochloride USP 1.50 Hydroxyethyl Cellulose 1.75 Benzyl Alcohol 1.00Trolamine 0.17 Total 100

Example 4 3.0% Naftifine Hydrochloride Gel

A gel formulation comprising 3.0% naftifine hydrochloride will beprepared in the same manner as the formulation in Example 1. Theformulation is shown in Table 4 below:

TABLE 4 Ingredient % w/w Purified Water USP 50.06 Polysorbate 20 NF 5.00Edetate Disodium USP 0.02 Ethanol 19.00 Propylene Glycol 20.00 NaftifineHydrochloride USP 3.00 Hydroxyethyl Cellulose 1.75 Benzyl Alcohol 1.00Trolamine 0.17 Total 100

In order to evaluate the gel preparations of Examples 1-3, the followingComparative Examples were prepared.

Comparative Example 1 1% Naftifine Hydrochloride Gel

Comparative Example 1 was prepared in a similar manner to thepreparations of Examples 1-3, except that Comparative Example 1comprises 1% naftifine hydrochloride, a carbomer as thickener instead ofa cellulose derivative, and 45.5%w/w ethanol. The formulation ofComparative Example 1 is provided in Table 5 below:

TABLE 5 Ingredient % w/w Purified Water USP 45.48 NaftifineHydrochloride USP 1.00 Ethanol 45.50 Carbomer 934P, NF 1.50 Polysorbate80 NF 5.00 Edetate Disodium USP 0.02 Diisopropanolamine 1.50 Total 100

The NDC code for commercially available NAFTIN® Gel, 1% is 40 g NDC0259-4770-40.

Comparative Example 2 1% Naftifine Hydrochloride Cream

Comparative Example 2 is a commercially available naftifinehydrochloride cream formulation marked as NAFTIN® Cream, 1%. Theformulation of Comparative Example 2 is provided in Table 6 below:

TABLE 6 Ingredient   Purified Water USP Polysorbate 60 IsopropylMyristate Stearyl Alcohol Cetyl Alcohol Cetyl Esters Wax NaftifineHydrochloride USP Sorbitan Monostearate Benzyl Alcohol Sodium Hydroxide

The NDC codes for NAFTIN® Cream, 1%, are as follows: 30 g NDC0259-4126-30; 60 g NDC 0259-4126-60; and 90 g NDC is 0259-4126-90.

Comparative Example 3 2% Naftifine Hydrochloride Cream

Comparative Example 3 is a commercially available naftifinehydrochloride cream formulation marked as NAFTIN® Cream, 2%. Theformulation of Comparative Example 3 is provided in Table 7 below:

TABLE 7 Ingredient   Purified Water USP Polysorbate 60 IsopropylMyristate Stearyl Alcohol Cetyl Alcohol Cetyl Esters Wax NaftifineHydrochloride USP Sorbitan Monostearate Benzyl Alcohol Sodium Hydroxide

The NDC code for NAFTIN® Cream, 2% is 45 g NDC 0259-1102-45.

Release Assay In Vitro Test

Studies entitled “Characterization of the Release Kinetics of Naftifineusing the in vitro Membrane Rate of Release Assay” were conducted undercontract by Cetero Research, Pre-Clinical Dermatology ResearchLaboratory, in Fargo, North Dakota, for MERZ Pharmaceuticals LLC. Thestudies were designed to determine the relative rates of release ofNaftifine from a reference and test formulations, using the FDA'sGuidance for Industry—“Non-sterile Semisolid Dosage Forms “Scale-Up andPost-approval Changes: Chemistry, Manufacturing, and Controls; In VitroRelease Testing and In Vivo Bioequivalence Documentation” known as theSUPAC-SS guidance.

Under this SUPAC-SS recommended membrane in vitro rate of releasemethod, each product was tested in sets of 6 diffusion chambers fittedwith Supor®-450 membranes (a polyethersulfone membrane). The receptorcompartment contained a solution consisting of 52% Ethanol and 48%Water. Six receptor solution aliquots were collected over a period of 6hours. The aliquots were analyzed for Naftifine content by HighPerformance Liquid Chromatography with a diode array detector (HPLC-UV).This measurement indicates the rate of membrane diffusion of a topicalproduct, and is seen as an industry standard in vitro method to predictrate of absorption on human skin in vivo following topical application.

Formulations of Comparative Examples 2 and 3

Commercially available naftifine hydrochloride cream formulation markedas NAFTIN® Cream, 1% of Comparative Example 2, and commerciallyavailable naftifine hydrochloride cream formulation marked as NAFTIN®Cream, 2% of Comparative Example 3, both include identical amounts ofeach of the inactive ingredients, i.e., polysorbate 60, isopropylmyristate, stearyl alcohol, cetyl alcohol, cetyl esters wax, sorbitanmonostearate, benzyl alcohol, and sodium hydroxide, with the onlydifference being that the 2% naftifine cream (NAFTIN® Cream, 2%)contains 1% less water than the 1% naftifine cream (NAFTIN® Cream, 1%).

Table 8 shows a comparison of the rate of membrane release of achievedwith the 1% (Comparative Example 2) and 2% (Comparative Example 3)Naftifine creams.

TABLE 8 Membrane Rate of Release Regression Slopes (μg/cm²/hr^(1/2))Reference naftifine 1% cream (Comparative Example 2) vs. naftitine 2%cream (Comparative Example 3) (n = 6) Naftifine 1% Naftifine 2% Chamber.Cream Chamber Cream 74 325.125 73 331.688 76 203.892 75 464.125 78214.711 77 454.141 80 302.451 79 435.799 82 328.250 81 468.310 84323.728 83 496.056 Mean ± SD 283.026 ± 57.932  Mean ± SD 441.686 ±57.372  Mean r² ± SD 0.983 ± 0.027 Mean r² ± SD 0.994 ± 0.004

As shown in Table 8, the mean rate of membrane release for the naftifine1% cream was 283 μg/cm²/hr^(1/2). The release rate of the naftifine 2%cream was 442 μg/cm²/hr^(1/2). These results suggest that doubling theactive ingredient in the same formulation would result in an almostdoubled release rate, i.e., approximately 1.6-fold increase in therelease rate.

Formulations of Example 1 or Example la and Comparative Example 1

Tables 9a and 9b show a comparison of the rate of membrane release forComparative Example 1 (NAFTIN Gel 1%), Example 1 (NAFTIN Gel 2%) andExample 1a (Alternative NAFTIN Gel 2%).

TABLE 9a Membrane Rate of Release Regression Slopes (μg/cm²/hr^(1/2))Comparative Example 1 vs. Example 1 (n = 6) Naftifine 1% Gel ComparativeNaftifine 2% Gel Chamber Example 1 Chamber Example 1 Chamber Naftifine1% Gel Chamber Naftifine 2% Gel 175 345.855 177 2621.582 178 360.562 1803102.955 181 324.761 183 3099.807 184 376.649 186 2679.009 187 362.804189 3069.425 190 324.698 192 2928.111 Mean ± SD 349.221 ± 21.337 Mean ±SD 2916.815 ± 216.917 Mean r² ± SD  0.996 ± 0.004 Mean r² ± SD  0.987 ±0.005

TABLE 9b Membrane Rate of Release Regression Slopes (μg/cm²/hr^(1/2))Comparative Example 1 vs. Example 1a (Alternative 2% Naftifine Gel) (n =6) Alternative Naftifine 1% Gel Naftifine 2% Gel Comparative Example 1aChamber Example 1 Chamber Alternative Chamber Naftifine 1% Gel ChamberNaftifine 2% Gel 175 345.855 176 2343.946 178 360.562 179 2332.724 181324.761 182 2307.076 184 376.649 185 2442.054 187 362.804 188 2296.518190 324.698 191 2247.276 Mean ± SD 349.221 ± 21.337 Mean ± SD 2328.266 ±65.161  Mean r² ± SD  0.996 ± 0.004 Mean r² ± SD  0.996 ± 0.004

In complete contrast to the findings demonstrated in the comparison ofthe Comparative Example 2 and Comparative Example 3 (1% and 2% Naftifinecream products) where doubling the API effectively doubled the rate ofrelease, in the case of the Comparative Example 1 and Example 1,doubling the API in the context of these altered gel formulationsincreased rate of release by an unexpectedly large amount. Likewise, inthe case of the Comparative Example 1 and Example l1a doubling the APIin the context of these altered gel formulations increased rate ofrelease by an unexpectedly large amount.

More specifically, the gel of Comparative Example 1 releases naftifineat a rate of 349 μg/cm²/hr^(1/2). The gel of Example 1, i.e., theformulation with hydroxyethyl cellulose replacing the carbomer andhaving a reduced alcohol content of 19% the release rate was 2917μg/cm²/hr^(1/2). The gel of Example 1a, i.e., with hydroxypropylcellulose replacing the carbomer, had a release rate of 2328μg/cm²/hr^(1/2.)

FIG. 1 is a graphical representation of the results obtained from therelease assay in vitro test. As shown in FIG. 1, the gel according toExample 1 exhibited substantially higher naftifine release rates whencompared to the gel of Comparative Example 1. Squares are used to denotethe Comparative Example 1 gel; triangles are used to denote the Example1 gel; circles are used to denote the Example 1a gel.

The magnitude of these changes was not expected in view of therelatively small increase resulting from the change in naftifineconcentration from 1 to 2% in the cream formulations of ComparativeExamples 2 and 3. The improvement is expected to have substantialbenefits on the efficiency of delivery of the anti-fungal compound intothe skin surface and may therefore also improve the activity andfunctionality of the product to mediate its antimicrobial activity.

Example 5 In vivo Maximal Use Study

Initial evaluation of the 2% naftifine gel according to Example 1 wasconducted in a Maximal Use Study in humans. The study had the followinggoals: (1) to quantify the pharmacokinetics of Example 1 in subjectswith Tinea pedis under maximal use conditions for 2-weeks of once dailyapplications; (2) to evaluate efficacy of Example 1 after 2-weeks ofonce daily applications and 2-weeks after last application; to evaluatesafety and tolerability of Example 1 throughout the study.

The study was an Open-label, single center, multiple applications to thefeet, Phase 1 study designed to quantify the pharmacokinetic (PK)profile in plasma and urine of 2-weeks of once daily application ofExample 1.

Maximal use conditions defined as application of a total of 4 grams (2grams/foot) of Example 1 in the morning for 2-weeks. Example 1 isapplied in a thin layer to the affected area plus a margin of about 0.5inches of healthy skin. PK blood and PK urine samples were obtained onDays 1 and 14 for 24 hours. Efficacy assessments for Example 1 werecarried out on Days 7, 15, and 28. Safety evaluation carried outthroughout the entire trial.

The study enrolled 32 participants, and all subjects had both feetinfected with Tinea pedis, 31 (96.9%) subjects had both interdigital andmoccasin type of Tinea pedis, and 30 (93.8%) subjects completed study.PK and safety data was excellent leading to the conclusions that underconditions of Maximal Use, Example 1 was well tolerated by all subjects.

The most stringent endpoint for anti-fungal products known as the“Complete Cure Rate” is defined as negative mycology results(dermatophyte culture and potassium hydroxide staining (KOH) from acentral laboratory and negative clinical signs and symptoms of disease(absence of erythema, scaling, and pruritus)). In Tinea pedis which ismore difficult to cure than other skin fungal infections the CompleteCure Rate mediated by Comparative Example 3 (2% naftifine cream), rangedfrom 14.3% in a maximal use Phase 1 study to 17.7% in a morecomprehensive Phase 3 study. Surprisingly, the Example 1 (naftifine 2%gel), tested in the same Phase 1 maximal use study mediated a CompleteClinical cure rate of 59.4%, which is substantially greater than anycure rate obtained for naftifine products previously. Since theconcentration of active naftifine in the cream and gel is equivalent,therefore the substantially improved clinical efficacy must be due tothe formulation improvement of Example 1. Taken together with theevidence obtained from the rate of release studies may indicate that theformulations described herein, for example, the formulations of Examples1-3, are capable of mediating substantially better clinical effect andantifungal benefits for the patient.

Example 6 Safety and Efficacy Study: Study Design

The formulation described in Example 1 was evaluated in 2 separate6-week, double-blind, randomized placebo-controlled, multicenter,parallel group phase 3 studies comparing Example 1 to a placebo vehiclein the treatment of Tinea pedis. In each study, approximately 850-860subjects were planned to be enrolled in a 2:1 ratio (Example 1: placebo)so as to obtain approximately 600 (400:200) evaluable subjects withpositive baseline cultures (after accounting for an assumed 30% culturefailure during screening).

The objectives of these studies were to evaluate the efficacy and safetyof Example 1, applied once daily for 2 weeks, when compared to placebofor 2 weeks in the treatment of subjects with Tinea pedis in independentPhase III clinical trials.

In each study, 3 analysis populations were used for summarizing subjectsin the trial, depending on whether the summaries were for safety orefficacy purposes. These were: (1) The Safety Evaluation Set (SES)comprised subjects who received study medication at least once (2) TheFull Analysis Set (FAS) was the subset of the SES who had positiveculture results at baseline and (3) The Per-Protocol Set (PPS) who werecomprised of subjects in the FAS who did not have any major protocoldeviations during the trial.

In study 1: Eight hundred and fifty nine (859) subjects belonged to theSES, while 613 subjects belonged to the FAS and 509 subjects belonged tothe PPS. Two hundred and thirteen (213) FAS subjects had at least oneprotocol deviation each. There were a total of 330 protocol deviationsdistributed among these 213 subjects. The most common protocoldeviations were the following: Visit 4 out of window (64 occurrences);Visit 3 out of window (35 occurrences); Visit 2 out of window (32occurrences) and; Visit 3 missed (22 occurrences). One hundred and nine(109) of the 213 FAS subjects did not have a major protocol deviationand therefore were retained in the PPS.

In study 2: Eight hundred and fifty five (855) subjects belonged to theSES, while 561 subjects belonged to the FAS and 436 subjects belonged tothe PPS. Two hundred and thirteen (213) FAS subjects had at least oneprotocol deviation each. There were a total of 125 subjects who wereremoved from the PPS.

Efficacy Results: Primary Efficacy

The primary efficacy variable was the percentage of subjects in theExample 1 group or placebo group with complete cure of interdigitalTinea pedis by Week 6. Complete cure was defined as negative mycologyresults from the central laboratory (negative dermatophyte culture andnegative Potassium Hydroxide (KOH) staining) and absence of erythema,scaling, and pruritus (grade 0 for each).

In order to compare complete cure between the Example 1 treatment groupand the placebo treatment group by Week 6, the following one-sidedhypothesis test was carried out: H_(o) (null): p₁=p_(o) versus H₁(alternate): p₁>p_(o) where p_(o) was the proportion of complete cure inthe placebo treatment group and p₁ was the proportion of complete curein the Example 1 treatment group.

The primary efficacy analysis evaluated the superiority of Example 1over placebo using the general association Cochran-Mantel-Haenszel (CMH)test after stratification by (pooled) clinical site. This test wasconducted with the FAS (using the Missing Value Treated as TreatmentFailure, MVTF as the primary missing value imputation method) at aone-sided level of significance of α=0.025. The MVTF method for missingprimary and most important secondary efficacy variables imputed missingpost-baseline data as not having complete cure, mycological cure ortreatment effectiveness.

TABLE 10 Primary Efficacy Variable-Complete Cure By Week 6 (MVTFImputation) Full Analysis Set Primary Efficacy Example 1 PlaceboVariable (N = 400) (N = 213) Complete Cure n (%) 104 (26.0) 7 (3.3)p-value [1] <0.0001 Note: % = (n/N) × I00. [1] Comparison of completecure for Example 1 versus Placebo from one-sided CMH test with (pooled)site as stratification variable.

TABLE 11 Primary Efficacy Variable Complete Cure at Week 6 (MVTFImputation) Per-Protocol Set Primary Efficacy Example 1 Placebo Variable(N = 329) (N = 180) Complete Cure n (%) 93 (28.3) 5 (2.8) p-value [1]<0.0001 Note: %—(n/N) × 100. [I] Comparison of complete cure for Example1 versus Placebo from one-sided CMH test with (pooled) site asstratification variable.

For the FAS subjects (using the MVTF missing value imputation method),the complete cure rates in the Example 1 and Placebo treatment groupswere 104/400 (26.0%) and 7/213 (3.3%) respectively. The test statistic(CMH) used to compare the proportion of complete cure in Example 1 tothat of Placebo proves that Example 1 is statistically superior toPlacebo, i.e., the null hypothesis is rejected in favor of the alternatehypothesis. These results are corroborated using the PPS where 93/329(28.3%) and 5/180 (2.8%) of complete cure in the Example 1 and Placebotreatment groups were obtained.

Very similar positive results were seen in the second identical study.Without recapitulating all results and data, a brief synopsis revealed aPrimary Efficacy Variable—Complete Cure at Week 6 (MVTF Imputation) Fullanalysis set of 64/382 patients ((16.8%) in the Example 1 treated groupversus 3/179 patients (1.7%) in the placebo group (p<0.001)). PrimaryEfficacy Variable—Complete Cure at Week 6 (MVTF Imputation) of the PerProtocol Set (PPS) demonstrated a complete cure in 59/296 (19.9%) in theExamplel treated group versus 3/140 patients (2.1%) in the Placebotreated group.(p<0.001).

Secondary Efficacy

The secondary efficacy variables were the following: Mycological Cure ofinterdigital Tinea pedis defined as negative KOH result and negativedermatophyte culture by Week 6; and Effective Treatment of interdigitalTinea pedis defined as negative KOH, negative culture, and erythema,scaling, and pruritus scores of 0 or 1 by Week 6.

If the test on the primary efficacy variable yielded a statisticallysignificant result (i.e. p=0.025 for a rejection of the null hypothesisto occur), then the most important secondary efficacy variables(mycological cure at Week 6 and effective treatment by week6) wassimultaneously tested applying adjustment for the level of significancea using the Hochberg's step-up procedure (one-sided CMH test atα=0.0125) to evaluate superiority of Formulation 1 over placebo on theFAS (using the MVTF imputation). This sequential testing accounted formultiplicity between the primary efficacy variable (first stage) and thetwo most important secondary efficacy variables (second stage).

TABLE 12 Secondary Efficacy Variables-Mycological Cure and TreatmentEffectiveness by Week 6 (MVTF Imputation) Full Analysis Set SecondaryEfficacy Example 1 Placebo Variable (N = 400) (N = 213) Mycological Curen (%) 235 (58.8) 22 (10.3) p-value [1] <0.0001 Treatment Effectiveness n(%) 203 (50.8) 15 (7.0)  p-value [1] <0.0001 Note: = (n/N) × 100. [1]Comparison of mycological cure or treatment effectiveness for Example 1versus Placebo from one-sided CMH test with (pooled) site asstratification variable.

Since the null hypothesis corresponding to the primary efficacy analysiswas rejected, the hypotheses corresponding to the secondary efficacyvariables (mycological cure and treatment effectiveness) were tested.The CMH test was also used as the test statistic for the comparisons.Both unadjusted and adjusted (using Hochberg's step-up procedure) wereused. The unadjusted and Hochberg-adjusted p-values for mycological cureand treatment effectiveness were both statistically significant.Mycological cure rate was 235/400 (58.8%) and 22/213 (10.3%) amongsubjects in the Example 1 and Placebo treatment groups respectively.Treatment effectiveness was accomplished among 203/400 (50.8%) and15/213 (7.0%) of subjects in the Example 1 and Placebo treatment groupsrespectively.

Again, these results were confirmed in the second independent phase IIIstudy. To summarize, the Mycological Cure rates and Treatmenteffectiveness at Week 6 (MTVF Imputation) in the Full Analysis setrevealed 250/382 (65.4%) vs. 25/179 (14.0%) mycological cure rates forExample 1 vs. Placebo respectively. Similarly, 207/382 (54.2%) vs.11/179 (6.1%) Treatment Effectiveness comparing Example 1 to Placebo,respectively. Each of these endpoints demonstrated statisticallysignificance (p>0.001) using a one-sided CMH test with (pooled) site asstratification variable.

Based on these results, a clear improvement in efficacy can be seen tobe afforded by Example 1. A direct comparison to Complete Cure ratesfollowing identical treatment regimes (QD for 2 weeks application) withComparative Example 3 conducted as part of phase III clinical studiesfor the approval of this product resulted in a Complete Cure ratedifferential of 11.1% between vehicle (placebo) and the ComparativeExample 3. In contrast, in the two studies outlined above, Complete CureRates from Example 1 were substantially better, generating a CompleteCure average differential of 19% between vehicle (placebo) and Example 1difference in complete cure rate can be attributed to the differencebetween the formulation/excipients of Example 1 and Comparative Example3 since the active naftifine concentrations in both products areidentical (2% naftifine hydrochloride).

Efficacy for Moccasin Tinea Pedis

Further demonstration of the superiority of the formulation of Example 1is offered by the clinical data resulting from treatment ofMoccasin-type Tinea pedis. In the previously outlined study in subjectswho had moccasin type Tinea pedis in addition to interdigital type Tineapedis, their efficacy is descriptively summarized based on completecure, mycological cure and treatment effectiveness by Week 6 based onobserved data below.

In study 1 Complete cure in the moccasin infected area of the foot was33/152 (21.7%) and 1/78 (1.3%) following treatment with Example 1 orplacebo respectively. Mycological cure was observed among 92/151 (60.9%)and 5/78 (6.4%) subjects in the Example 1 and Placebo treated subjectsrespectively, in the moccasin affected areas of the foot. Treatmenteffectiveness was observed among 77/151 (51.0%) and 1/78 (1.3%) subjectsin the Example 1 and Placebo treated subjects respectively, in themoccasin affected areas of the foot.

In study 2 Complete cure in the moccasin infected area of the foot was25/144 (17.4%) and 0/72 (0.0%) following treatment with Example 1 orplacebo respectively. Mycological cure was observed among 100/143(69.9%) and 10/72 (13.9%) subjects in the Example 1 and Placebo treatedsubjects respectively, in the moccasin affected areas of the foot.Treatment effectiveness was observed among 73/143 (51.0%) and 8/72(11.1%) subjects in the Example 1 and Placebo treated subjectsrespectively, in the moccasin affected areas of the foot.

This data is very significant since prior to the present invention therewere no known topically administered antifungal agents which achieve anysubstantial Complete Cure activity in this disease setting.

Indeed, as direct evidence, previous phase III studies with ComparativeExample 3 (identical 2% naftifine hydrochloride, cream) demonstrated noeffective ability to offer any Complete Cure of Moccasin-type Tineapedis.

Safety

In both of these large clinical studies Example 1 was deemed to be verywell tolerated and had an excellent safety profile. The incidence ofTEAEs (Treatment-associated adverse events) related to treatment were12/572 (2.1%) and 9/571 (1.6% compared to 2/287 (0.7%) and 2/284 (0.7%)in the placebo groups of Study 1 and 2 respectively.

In previous clinical trials of the Comparative Example 1, comprising 1%Naftifine Hydrochloride, a carbomer as thickener instead of a cellulosederivative, and 45.5%w/w ethanol, the incidence of Application Site AEs(adverse events) were as follows: burning/stinging (5.0%), itching(1.0%), erythema (0.5%), rash (0.5%), and skin tenderness (0.5%).

In stark contrast, the Application Site AEs associated with Example 1 asrecorded in the two phase III clinical studies described herein wereremarkably infrequent. In fact, Application Site AEs did not even reachthe 1% incidence threshold required for reporting, and less than 1% ofpatients treated with Example 1 exhibited any of the following symptoms:pain, application site dermatitis, pruritus, dryness, erosion, fissure,paraesthesia, rash, swelling or warmth.

These results indicate that Example 1 was extremely well toleratedduring application, and is a major improvement over the previousComparative Example 1 in terms of an excellent application site safetyprofile and absence of adverse events when applied to thefungal-affected area.

Conclusion

The primary efficacy objective of this study was met. Example 1 wasresoundingly statistically superior to Placebo (p<0.025) in theproportion of subjects attaining complete cure. The results of thisstudy provided clinical evidence that the Example 1 clinical trial had acomplete cure of all signs and symptoms in 26% (Study 1) and 17% (Study2) of patients after 2 weeks treatment (once daily) resulting in aclinical meaningfulness and practical relevance to patients and healthcare providers. Significant results were also obtained for the mostimportant secondary efficacy variables (mycological cure and treatmenteffectiveness). Of further importance is the efficacy analysis ofsubjects with moccasin type Tinea pedis. Complete cure among subjectswith moccasin-type Tinea pedis in the Example 1 group was 22% (Study 1)and 17% (Study 2)—a clinically significant outcome considering that thattreatment for moccasin type Tinea pedis previously has required an oralanti-fungal medication. Example 1 was well tolerated, generating an AEprofile where local application site AEs were less than 1% of thetreated population. This absence of application site AEs indicates anextremely well tolerated topical product, and one that appears to besignificantly improved over comparative examples 1 and 2. The minimalapplication site AE profile of this formulation is expected to be verybeneficial in the case of active fungal infection where the skin isfrequently inflamed, red, and highly sensitive to topical interventions.Such a combination of potent clinical activity and an excellenttolerability profile confirm Example 1 to be unexpectedly superior overexisting products.

Example 7 Skin Deposition of Topically Applied Naftifine

Studies were conducted in patients to assess the amount of naftifineavailable in the stratum corneum following daily topical application ofExample 1 (2% Naftifine Gel) and Comparative Example 3 (2% NaftifineCream) for a period of 14 days.

This was an open-label, intra-subject, single-exposure study on healthyadult male and female subjects comparing the amount of naftifine thatwas absorbed into the stratum corneum following topical application ofthe different formulations. Six subjects were treated with theformulation of Example 1 and 6 subjects were treated with theformulation of Comparative Example 3. Individuals who met allinclusion/exclusion criteria were qualified for enrollment into thetreatment phase of the study.

Enrolled subjects had a total of twelve 8-cm² (2 cm×4 cm, long sideparallel to spine) test application sites demarcated on the upper back(randomly assigned and as 2 rows of 3 on one side and 2 rows of 3 on theother side of the spine). Of these, a total of 11 sites were dosed withthe test formulations once daily (5.0 μL/cm² or 40 μL per site) for 1 to14 days. A final site remained untreated to serve as the non-dosedcontrol site. Applications were made using an EPPENDORF repeat dosepipette. The applied dose was then evenly spread and gently rubbed intothe test site with a glass rod.

On days 2, 3, 4, 5, 6, 7, 15, 22, 29, 36, and 43, a selected test sitewas tape stripped (adhesive tape applied to the skin and then removedtaking with it a thin layer of the strateum corneum which was thenanalyzed for content of naftifine). The tape used was Transpore Tape(3M), measuring (nominally) 1″×2″ to allow tape stripping of the dosedarea including a small margin around the application site. Each tapestrip was applied to the test site and gently but firmly pressed with arubber brayer across the entire site of application for 5 seconds toensure complete contact. The strip was removed with 1 smooth continuousmotion over a 1-2 second duration. After each set of applications(sequential grouped sets of 5, 5, 5, 5, and 5 tape strips) the directionof tape stripping and rolling were reversed (ie, top to bottom, bottomto top). A total of 25 individual sequential fresh strips were appliedto each test site. The sequential sets of strips (1-5, 6-10, 11-15,16-20, and 21-25) were placed into pre-labeled glass vials and sealedfollowing collection. At the completion of each study day's activity,the vials were transferred and stored at −20° C. until processed by theanalytical laboratory. The tape strips from each side were processed andquantified for amount of naftifine present. This study was designed todetermine the amount of naftifine that penetrated into the stratumcorneum from 1 to 14 days of application, and its elimination from thestratum corneum over 28 days following the last dose application. Thequantification of naftifine present in the stratum corneum tape stripsamples was measured using extraction and analytical methods developedfor these samples, and according to Cetero Research AnalyticalLaboratory's Standard Operating Procedures and FDA Guidelines.

Table 13 shows a comparison of the rate deposition of naftifine into theskin of patients following once-daily dosing of Example 1(2% NaftifineHydrochloride Gel) and Comparative Example 3 (2% Naftifine HydrochlorideCream) onto the skin for a period of 14 days. These pharmacokineticresults represent the Mean and Standard Deviation results by treatmentof total recovered naftifine from the tape strip samples normalized toarea dosed (ng/mL).

TABLE 13 Skin Deposition Rates of Naftifine (ng/mL) comparing theformulation of Example 1 (2% Naftifine Hydrochloride Gel) and theformulation of Comparative Example 3 (2% Naftifine Hydrochloride Cream)following once-daily application for a period of 14 days (N = 6 patientsper sample group) Naftifine 2% Cream Naftifine 2% Gel Day ComparativeExample 3 Example 1 Day Naftifine 2% Cream Naftifine 2% Gel 1 0.097 ±0.212 0.009 ± 0.011 2 762.67 ± 874.96 1150.65 ± 1976.45 3 1045.47 ±1823.31 1509.98 ± 2421.35 4 281.49 ± 310.64 751.73 ± 908.97 5 254.24 ±338.08 831.31 ± 888.05 6 151.70 ± 121.89 457.49 ± 552.38 7 161.63 ±221.87 534.15 ± 512.86 15 321.63 ± 245.90 199.97 ± 172.83 22 159.98 ±231.79 126.39 ± 212.22 29  66.60 ± 157.38 5.45 ± 5.08 36 20.97 ± 29.28128.62 ± 201.11 43 2.87 ± 3.39 20.30 ± 28.98

With regard to safety results, no serious adverse events were reportedover the course of this study. Overall, the most common adverse eventsreported were application site pain and application site pruritusattributable to site tape stripping. Application site pain was reportedon 1 occasion by 3 (3/12) subjects (25.0%) but was considered by theInvestigator to be not related to the test products. Application sitepruritus was reported on at least 1 occasion by 2 (2/12) subjects(16.7%) and was considered by the Investigator to be related to the testproducts on 1 occasion and not related to the test products on 2occasions.

As shown in Table 13, the data indicate the presence of naftifine in thetape strips on all sample collection days. However, the amount ofnaftifine recovered from the tape strips was higher following treatmentwith Example 1 (naftifine 2% gel) from Day 2 to 7 and from Day 36 to 43,while the amount of naftifine recovered from the tape strips wasslightly higher following treatment with Comparative Example 3(naftifine 2% cream) from Day 15 to 29. The maximum amount of naftifineHC1 recovered in the tape strips occurred on Day 3 for both testarticles before decreasing (despite continuation of dosing through Day14) through the remaining duration of study conduct (Day 43).

Both with Example 1 (naftifine 2% gel) and Comparative Example 3(naftifine 2% cream) were well tolerated as single daily siteapplications of 5.0 μL/cm2 (40 μL total/8 cm² site) applied topically tohealthy adult subjects for 1 to 14 consecutive days.

In conclusion, these data demonstrate that the rate with which theactive naftifine agent is deposited into the skin of a patient is morerapid/efficient when delivered via Example 1 (naftifine 2% gel) comparedto Comparative Example 3 (naftifine 2% cream), and this difference inthe efficiency of delivery can be solely attributed to inherentdifference in the formulation of the delivery vehicle.

Example 8 Corticosteroid Gel Formulations

The following Tables provide examples of fluticasone formulations.

General Preparation of Fluticasone Gel Formulations

Fluticasone gel formulations can be prepared in the same manner asdescribed above for Naftifine gel formulations (see “General Preparationof Naftifine Gel Formulations,” supra). That is, one can replacenaftifine with fluticasone, or a salt or ester thereof (e.g.,fluticasone propionate), to arrive at a fluticasone gel formulation ofthe present invention. In some embodiments, a fluticasone gelformulation is manufactured in the manner described above for naftifine,albeit with diethylene glycol monoethyl ether used in place of ethanol.In some embodiments, a fluticasone gel formulation is manufactured inthe manner described above for naftifine, albeit with diethylene glycolmonoethyl ether used in combination with ethanol. In some embodiments, afluticasone gel formulation is manufactured in the manner describedabove for naftifine, albeit without diethylene glycol monoethyl ether orethanol, in which case the fluticasone, or salt or ester thereof (e.g.,fluticasone propionate), can be added to propylene glycol. In someembodiments, a fluticasone gel formulation is manufactured in the mannerdescribed above for naftifine, albeit without adding trolamine. In someembodiments, the fluticasone, or salt or ester thereof, is entirelydissolved in the gel formulation. In some embodiments, the fluticasoneor salt or ester thereof is not entirely dissolved in the gelformulation.

TABLE 24 Fluticasone Formulation (Gel formulation 1, 0.025%) IngredientFormula % Active Ingredients: Fluticasone Propionate 0.025 Alsocontains: Purified Water 66.705 Propylene Glycol 20.0 Ethanol 5.0Polysorbate 20 5.0 Hydroxyethyl Cellulose 1.75 Edetate Disodium 0.02Diethylene Glycol 1.5 Monoethyl Ether Benzyl Alcohol — 100.00 pH 5.43

TABLE 25 Fluticasone Formulations Ingredient Formula % Formula % ActiveIngredients: Fluticasone Propionate 0.05 0.025 Also contains: PurifiedWater 53.18 53.205 Propylene Glycol 20.0 20.0 Ethanol 19.0 19.0Polysorbate 20 5.0 5.0 Hydroxyethyl Cellulose 1.75 1.75 Benzyl Alcohol1.00 1.00 Edetate Disodium 0.02 0.02 100.00 100.00 pH 5.5 5.49

TABLE 26 Fluticasone Formulations Ingredient Formula % Formula % ActiveIngredients: Gel formulation 2, 0.025% Fluticasone Propionate 0.0250.025 Also contains: Purified Water 71.705 65.205 Propylene Glycol 20.020.0 Ethanol — 8.0 Polysorbate 20 5.0 5.0 Hydroxyethyl Cellulose 1.751.75 Benzyl Alcohol — — Edetate Disodium 0.02 0.02 Diethylene Glycol 1.5— Monoethyl Ether 100.00 100.00 pH 5.78 5.43

TABLE 27 Fluticasone Propionate Gel A B Active Ingredients: FluticasonePropionate 0.05 0.025 Also contains: Ethanol NA NA Benzyl Alcohol 1.001.00 Edetate Disodium 0.02 0.02 Hydroxyethyl Cellulose 1.75 1.75Polysorbate 20 5.00 5.00 Propylene Glycol 41.00 41.025 Purified Water51.01 51.01 Trolamine 0.17 0.17 pH 8.17 8.01 Viscosity (#6 @ 10 rpm)65,300 cP 62,900 cP NOTE: pH before Trolamine addition for all sampleswas approximately pH 5.4-5.5

TABLE 28 Fluticasone Formulation A Ingredient Formula % ActiveIngredients: Fluticasone Propionate 0.025 Also contains: Purified Water73.205 Propylene Glycol 20.0 Ethanol — Polysorbate 20 5.0 HydroxyethylCellulose 1.75 Benzyl Alcohol — Edetate Disodium 0.02 Diethylene GlycolMonoethyl Ether 100.00

TABLE 29 Fluticasone Formulation B Ingredient Formula % ActiveIngredients: Fluticasone Propionate 0.025 Also contains: Purified Water70.705 Propylene Glycol 20.0 Polysorbate 20 5.0 Hydroxyethyl Cellulose1.75 Benzyl Alcohol 1.0 Edetate Disodium 0.02 Diethylene Glycol 1.5Monoethyl Ether 100.00

TABLE 30 Fluticasone Formulation C Ingredient Formula % ActiveIngredients: Fluticasone Propionate 0.050 Also contains: Purified Water70.680 Propylene Glycol 20.000 Polysorbate 20 5.000 HydroxyethylCellulose 1.750 Benzyl Alcohol 1.0 Edetate Disodium 0.02 DiethyleneGlycol 1.5 Monoethyl Ether 100.00

TABLE 31 Fluticasone Formulation D Ingredient Formula % ActiveIngredients: Fluticasone Propionate 0.100 Also contains: Purified Water70.630 Propylene Glycol 20.000 Polysorbate 20 5.000 HydroxyethylCellulose 1.750 Benzyl Alcohol 1.0 Edetate Disodium 0.02 DiethyleneGlycol 1.5 Monoethyl Ether 100.00

Preliminary stability studies demonstrate that the formulations shown inTables 24, 25, and 26 are stable for up to one month at ambienttemperature (ca. 22° C.), for at least one week at elevated temperatures(ca. 50° C.), and for at least one week at lowered temperatures (ca. 5to 8° C.).

Release Assay In Vitro Test

A study entitled “In Vitro Release of Fluticasone Propionate from TwoReference and Four Test Fluticasone Propionate Formulations using the InVitro Release Test (IVRT) Method” was conducted by PRACS Institute inFargo, North Dakota, for Merz Pharmaceuticals, LLC, in Greensboro, N.C.The study design was based on the principles of the U.S. FDA's SUPAC-SSGuidance document. The study utilized a single center, open label, InVitro Release Test (IVRT) equivalence comparison study, of 2 referenceand 4 test formulation lots containing Fluticasone propionate, using anin vitro synthetic membrane model. The reference products consisted of acream (0.05%) and a lotion (0.05%) lot. The test products consisted of 4gel formulations (0.05% and 0.025%). A pilot study was conducted toconfirm the selected procedures were suitable for the pivotal study(i.e. receptor solution, synthetic membrane, dosing area, diffusion cellsize, and sampling time points).

The rates of release of Fluticasone propionate from 2 reference products(1 lotion 0.05% and 1 cream 0.05% lot) and 4 gel test formulations usingthe In Vitro Release Test (IVRT) method in a manner compatible with theSUPAC-SS Guidance, as applicable, are provided in the below Tables. TheNDC code for commercially available Fluticasone Propionate Cream, 0.05%,30 g tube, is NDC 45802-222-11; the ANDA code for commercially availableFluticasone Propionate Cream, 0.05%, is ANDA # 076793. The NDC code forcommercially available Cutivate® lotion, 0.05%, 60 mL bottle, is NDC10337-434-60; the NDA code for commercially available Cutivate® lotion,0.05%, is NDA # 021152. As the below data illustrate, it wassurprisingly found that formulations of the present invention have asuperior ability to release active drug as compared to existingreference products (see FIG. 3 for a graphical representation of theresults).

TABLE 30a Rate of Release Regression Slopes (μg/cm2/hr½) FluticasonePropionate Cream Reference, Cutivate Lotion 0.05% Reference, 0.05%0.025% Gel (NDC 45802-222- (NDC 10337-434- (Table 27, 11) 60) column 2)r² 0.998 ± 0.002 0.997 ± 0.003 0.992 ± 0.004 Slope 15.05 ± 1.88  6.71 ±0.53 15.98 ± 0.69  (Mean ± SD)

TABLE 30b Rate of Release Regression Slopes (μg/cm2/hr½) FluticasonePropionate Gel formulation 1, 0.05% Gel Gel formulation 2, 0.025% (Table27, 0.025% (Table 24) column 1) (Table 26, column 1) r² 0.981 ± 0.0020.987 ± 0.003 0.984 ± 0.003 Slope 22.34 ± 0.89  26.03 ± 1.05  21.09 ±1.23  (Mean ± SD)Release Assay In Vitro Test of Fluticasone Formulations B, C, and D

A study entitled “Method Development and Evaluation of In Vitro Release(SUPAC-SS) of Fluticasone Propionate” was conducted based on theprinciples of the U.S. FDA's SUPAC-SS Guidance document.

The rates of release of the three formulations are depicted graphicallyin FIG. 4. Whereas fluticasone Formulation B showed in principal theexpected release characteristics similar to Gel Formulation 2 (Table 26,column 1), Formulation C showed a faster release rate due to the higherfluticasone propionate concentration. Furthermore, it was surprisinglyfound that Formulation D (0.1 wt % fluticasone propionate) showed anoverproportional faster release compared to 0.05 wt % and 0.025 wt %fluticasone formulations.

The present subject matter being thus described, it will be apparentthat the same may be modified or varied in many ways. Such modificationsand variations are not to be regarded as a departure from the spirit andscope of the present subject matter, and all such modifications andvariations are intended to be included within the scope of the followingclaims.

The invention claimed is:
 1. A gel composition for topicaladministration comprising: (i) naftifine or a pharmaceuticallyacceptable salt thereof, present in an amount of from about 0.5 wt % toabout 4 wt %; (ii) a solvent comprising a glycol solvent component andan alkyl alcohol solvent component, present in an amount of from about10 wt % to about 50 wt %; (iii) a hydroxy cellulose, present in anamount of from about 0.75 wt % to about 2.25 wt %; (iv) a polysorbatesolubilizing agent present in an amount of from about 3 wt % to about 8wt %; (v) an amine pH adjuster in an amount of from about 0.12 wt % toabout 0.23 wt %; and one or more of: water, a preservative, a chelatingagent, a coloring agent, and a fragrance.
 2. The gel composition ofclaim 1, wherein the naftifine or a pharmaceutically acceptable saltthereof is present in an amount of from about 1.0 wt % to about 3.0 wt%.
 3. The gel composition of claim 1, wherein the glycol solvent ispresent in an amount of about 18 wt % to about 22 wt %.
 4. The gelcomposition of claim 3, wherein the glycol solvent is propylene glycol.5. The gel composition of claim 1, wherein the alkyl alcohol is presentin an amount of from about 17 wt % to about 22 wt %.
 6. The gelcomposition of claim 5, wherein the alkyl alcohol is ethanol.
 7. The gelcomposition of claim 1, wherein the hydroxy cellulose is hydroxyethylcellulose.
 8. The gel composition of claim 1, wherein the polysorbatesolubilizing agent is Polysorbate
 20. 9. The gel composition of claim 1,wherein the polysorbate solubilizing agent is Polysorbate
 80. 10. Thegel composition of claim 1, wherein the naftifine, or pharmaceuticallyacceptable salt thereof, is naftifine hydrochloride.
 11. The gelcomposition of claim 1, wherein: the naftifine, or a pharmaceuticallyacceptable salt thereof, is present in an amount of about 2.0 wt %, theglycol solvent is present in an amount of about 20 wt %, the alkylalcohol solvent is present in an amount of about 19 wt %, the hydroxycellulose is present in an amount of about 1.75 wt %, and thepolysorbate solubilizing agent is present in an amount of about 5 wt %.12. The gel composition of claim 11, wherein the glycol solvent ispropylene glycol.
 13. The gel composition of claim 11, wherein thealcohol solvent is ethanol.